Processes for the diazotization of 2,5-dichloroanilines

ABSTRACT

The present disclosure relates, in general, to processes for converting 2,5-dichloroaniline compounds to the corresponding 2,5-dichlorobenzenediazonium compounds, and further relates to processes for the preparation of 2,5-dichlorophenol which is a key intermediate used in the manufacture of dicamba.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of Ser. No. 15/106,072 filed on Jun.17, 2016, which is a 371 National Stage Application of InternationalApplication No. PCT/US2014/070764, filed Dec. 17, 2014, which claimspriority to U.S. Provisional Application No. 61/917,605 filed Dec. 18,2013, which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present disclosure relates, in general, to processes for converting2,5-dichloroaniline compounds to the corresponding2,5-dichlorobenzenediazonium compounds, and further relates to processesfor the preparation of 2,5-dichlorophenol which is a key intermediateused in the manufacture of dicamba.

BACKGROUND OF THE INVENTION

3,6-Dichloro-2-methoxybenzoic acid (also known by its common namedicamba) is a highly effective and commercially important herbicide thatis useful for controlling a wide variety of unwanted vegetation,including agricultural weeds. Convenient and economical methods ofpreparing dicamba, therefore, are of significant commercial importance.

A number of synthetic routes for the preparation of dicamba have beenreported in the literature. One such route generally involves theconversion of 2,5-dichloroaniline to dicamba as shown in Scheme 1 below:

See, e.g., U.S. Pat. No. 4,161,611.

This route, however, typically requires certain process conditions (suchas fine milling of the 2,5-dichloroanaline starting material, use of alarge excess of sulfuric acid and/or concentrated sulfuric acid in thediazotizing step, etc.) in order to achieve an acceptable conversion ofthe 2,5-dichloroanaline to the 2,5-dichlorophenol on a commercial scale.The present disclosure provides improved processes that reduce oreliminate the need for such process conditions while still maintaining,or even improving, conversion of the 2,5-dichloroanaline to the2,5-dichlorophenol.

BRIEF DESCRIPTION OF THE INVENTION

The present disclosure relates to processes for converting2,5-dichloroaniline compounds to the corresponding2,5-dichlorobenzenediazonium compounds.

In one aspect, the present disclosure relates to a process for thepreparation of a compound corresponding in structure to Formula (IV):

or a salt thereof, wherein R¹ is as defined in the presentspecification, and wherein the process comprises contacting a compoundcorresponding in structure to Formula (III):

or a salt thereof, with a diazotizing agent in a reaction mediumcomprising sulfuric acid and an organic acid selected from the groupconsisting of C₂-C₆-alkanoic acids and halo-C₁-C₆-alkanoic acids togenerate a diazonium product mixture comprising the compound or salt ofFormula (IV).

In another aspect, the present disclosure relates to a process for thepreparation of a compound corresponding in structure to Formula (IV):

or a salt thereof, wherein R¹ is as defined in the presentspecification, and wherein the process comprises:

forming a reaction medium comprising sulfuric acid; an organic acidselected from the group consisting of C₂-C₆-alkanoic acids andhalo-C₁-C₆-alkanoic acids; and, optionally, a first amount of a compoundcorresponding in structure to Formula (III):

or a salt thereof; and

introducing into the reaction medium a second amount of the compound orsalt of the compound of Formula (III), and a diazotizing agent, togenerate a diazonium product mixture comprising the compound or salt ofFormula (IV).

In another aspect, the present disclosure relates to a process for thepreparation of a compound corresponding in structure to Formula (IV):

or a salt thereof, wherein R¹ is as defined in the presentspecification, and wherein the process comprises:

forming a reaction medium comprising sulfuric acid; an organic acidselected from the group consisting of C₂-C₆-alkanoic acids andhalo-C₁-C₆-alkanoic acids; and a compound corresponding in structure toFormula (III):

or a salt thereof; and

introducing into the reaction medium a diazotizing agent to generate adiazonium product mixture comprising the compound or salt of Formula(IV).

In another aspect, the present disclosure relates to a process as statedabove that further comprises hydrolyzing the compound or salt of Formula(IV) to a compound corresponding in structure to Formula (V):

or a salt thereof, wherein R¹ is as defined in the presentspecification.

In another aspect, the present disclosure relates to a process for thepreparation of a compound corresponding in structure to Formula (VI):

or a salt thereof, wherein the process comprises:

contacting a compound corresponding in structure to Formula (III-a):

or a salt thereof, with a diazotizing agent in a reaction mediumcomprising sulfuric acid and an organic acid selected from the groupconsisting of C₂-C₆-alkanoic acids and halo-C₁-C₆-alkanoic acids togenerate a diazonium product mixture comprising a compound correspondingin structure to Formula (IV-a):

or a salt thereof;

hydrolyzing the compound or salt of Formula (IV-a) to generate a phenolproduct mixture comprising a compound corresponding in structure toFormula (V-a):

or a salt thereof; and

carboxylating the compound or salt of Formula (V-a) to generate acarboxylated product mixture comprising a compound corresponding instructure to Formula (V-b):

or a salt thereof; and

converting the compound or salt of Formula (VI-b) to the compound orsalt of Formula (VI).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a bar chart illustrating the percent conversion (based onnormalized peak absorbance at 208 nm by HPLC) of 2,5-dichloroaniline to2,5-dichlorobenzenediazonium (quantified as 1,4-dichlorobenzene) as afunction of equivalents of sulfuric acid relative to the2,5-dichloroaniline.

FIG. 2 is a bar chart illustrating the percent conversion (based onnormalized peak absorbance at 208 nm by HPLC) of 2,5-dichloroaniline to2,5-dichlorobenzenediazonium (quantified as 1,4-dichlorobenzene) as afunction of equivalents of acetic acid relative to the2,5-dichloroaniline.

FIG. 3 is a bar chart illustrating the average percent conversion (basedon normalized peak absorbance at 208 nm by HPLC) of 2,5-dichloroanilineto 2,5-dichlorobenzenediazonium (quantified as 1,4-dichlorobenzene) as afunction of equivalents of sodium nitrite relative to the2,5-dichloroaniline.

DETAILED DESCRIPTION OF THE INVENTION

This written description uses examples to disclose the invention,including the best mode, and also to enable any person skilled in theart to practice the invention, including making and using any of thedisclosed salts, substances, or compositions, and performing any of thedisclosed methods or processes. The patentable scope of the invention isdefined by the claims, and may include other examples that occur tothose skilled in the art. Such other examples are intended to be withinthe scope of the claims if they have elements that do not differ fromthe literal language of the claims, or if they include equivalentelements.

I. DEFINITIONS

Section headings as used in this section and the entire disclosure arenot intended to be limiting.

Where a numeric range is recited, each intervening number within therange is explicitly contemplated with the same degree of precision. Forexample, for the range 6 to 9, the numbers 7 and 8 are contemplated inaddition to 6 and 9, and for the range 6.0 to 7.0, the numbers 6.0, 6.1,6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are explicitlycontemplated. In the same manner, all recited ratios also include allsub-ratios falling within the broader ratio.

The singular forms “a,” “an” and “the” include plural referents unlessthe context clearly dictates otherwise.

The term “about” generally refers to a range of numbers that one ofskill in the art would consider equivalent to the recited value (i.e.,having the same function or result). In many instances, the term “about”may include numbers that are rounded to the nearest significant figure.

Unless the context requires otherwise, the terms “comprise,”“comprises,” and “comprising” are used on the basis and clearunderstanding that they are to be interpreted inclusively, rather thanexclusively, and that Applicant intends each of those words to be sointerpreted in construing this patent, including the claims below.

The term “sodium nitrite_((aq))” refers to an aqueous solution of sodiumnitrite.

The term “sulfuric acid_((aq))” refers to an aqueous solution ofsulfuric acid.

The abbreviation “AcOH” means acetic acid.

The abbreviation “2,5-DCA” means 2,5-dichloroaniline.

The abbreviation “1,4-DCB” means 1,4-dichlorobenzene.

The abbreviation “2,5-DCD” means 2,5-dichlorobenzenediazonium.

The abbreviation “1,4-DCNB” means 1,4-dichloronitrobenzene.

The abbreviation “2,5-DCP” means 2,5-dichlorophenol.

II. DIAZOTIZATION OF 2,5-DICHLOROANILINES

The present disclosure relates, in part, to processes for diazotizing a2,5-dichloroaniline compound to provide the corresponding2,5-dichlorobenzenediazonium compound. In particular, the presentdisclosure relates to processes for diazotizing 2,5-dichloroaniline toprovide 2,5-dichlorobenzenediazonium. The 2,5-dichlorobenzenediazoniumprepared can be hydrolyzed to provide the corresponding2,5-dichlorophenol, a key intermediate used in the manufacture ofdicamba.

Among other process improvements, it has been discovered that2,5-dichloroaniline and its sulfate salt have improved solubility in areaction medium comprising sulfuric acid and an organic acid selectedfrom the group consisting of C₂-C₆-alkanoic acids (such as acetic acid)and halo-C₁-C₆-alkanoic acids (such as trifluoroacetic acid) relative toa corresponding reaction medium lacking the organic acid. It has beenfurther discovered that conducting the diazotization reaction in such areaction medium results in a more efficient and homogeneous conversionof the 2,5-dichloroaniline to the corresponding2,5-dichlorobenzenediazonium. Excellent conversions of the2,5-dichloroaniline to the 2,5-dichlorobenzenediazonium have beenachieved using an organic acid/sulfuric acid reaction medium.

Due to its cheaper cost relative to more expensive organic reagents,sodium nitrite (NaNO₂) frequently is selected as a diazotizing agent fordiazotization reactions conducted in an industrial setting. When sodiumnitrite is used as the diazotizing reagent, the reaction typically isconducted in an acid medium in order to generate nitrous acid which isthen consumed in the diazotizing step. Sulfuric acid (H₂SO₄) frequentlyis used as the acid medium for such diazotization reactions. Scheme 2below illustrates the hypothesized reaction pathway for the generationof nitrous acid from sodium nitrite in a sulfuric acid medium and thesubsequent generation of nitrosylsulfuric acid. As discussed later, thenitrosylsulfuric acid generated reacts with the 2,5-dichloroanilinestarting material to provide the 2,5-dichlorobenzenediazonium product.

It is believed that sodium nitrite 2 reacts with an equivalent ofsulfuric acid 1 to produce nitrous acid 3 and sodium bisulfate 4. Understrong acidic conditions, the nitrous acid 3 then reacts with sulfuricacid 1 to generate nitrosylsulfuric acid 5 and water 6.

When the diazotization reaction takes place in a sulfuric acid medium,the free 2,5-dichloroaniline (not the sulfate salt of2,5-dichloroaniline) serves as the nucleophile and reacts with thenitrosylsulfuric acid which serves as the electrophile. The solubilityof 2,5-dichloroaniline in concentrated and aqueous solutions of sulfuricacid is relatively low, and conversion of the 2,5-dichloroaniline to thecorresponding 2,5-dichlorobenzenediazonium is limited by suchsolubility. Therefore, a large amount of the sulfuric acid (and/orhigher concentrations of the sulfuric acid) generally is required toachieve an acceptable conversion and the process is not efficient forcommercial-scale manufacturing.

One approach suggested in the literature for addressing this problem hasbeen to mill the 2,5-dichloroaniline to a fine particle size in order toimprove solubility. U.S. Pat. No. 4,005,151, for example, describes ballmilling the 2,5-dichloroaniline starting material used in thediazotizing step.

Another approach suggested in the literature has been to useconcentrated sulfuric acid, or at least higher concentrations of aqueoussulfuric acid, as the reaction medium. U.S. Pat. No. 4,326,882, forexample, describes the use of concentrated sulfuric acid in thediazotizing step.

Use of an alternative mineral acid medium such as a hydrochloric acid(HCl) medium is not a satisfactory alternative. The solubility of2,5-dichloroaniline in concentrated and aqueous solutions ofhydrochloric acid, for example, also is relatively low and conversion ofthe 2,5-dichloroaniline to the corresponding2,5-dichlorobenzenediazonium is similarly limited by solubility. Inaddition, use of hydrochloric acid as the acid medium allows thechloride (Cl⁻) to compete as a nucleophile during the subsequenthydrolysis of the 2,5-dichlorodiazonium to the 2,5-dichlorophenolpotentially resulting in a 3-chloro substituent instead of the desired3-hydroxy substituent. Similarly, nitric acid and other mineral acidswould present the same problem, e.g., use of nitric acid as the acidmedium, to the extent even practical, would allow the nitrate (NO₃ ⁻) tocompete as a nucleophile during the subsequent hydrolysis of the2,5-dichlorodiazonium to the 2,5-dichlorophenol potentially resulting ina 3-nitro substituent instead of the desired 3-hydroxy substituent.Accordingly, sulfuric acid is generally preferred over other mineralacids when the 2,5-dichlorobenzenediazonium generated is to be furtherhydrolyzed to the 2,5-dichlorophenol.

Use of the organic acid/sulfuric acid reaction medium of the presentdisclosure provides several advantages over a conventional sulfuric acidreaction medium including the following:

(1) Excellent conversions of the 2,5-dichloroaniline to the2,5-dichlorobenzenediazonium are achieved.

(2) Additional processing of the 2,5-dichloroaniline starting material(e.g., fine milling such as ball milling) is not required to helpsolubilize the 2,5-dichloroaniline.

(3) Sulfuric acid handling requirements are reduced as a lower volume ofsulfuric acid is needed for the diazotization reaction.

(4) Where the overall process also includes a hydroxylation step inwhich the 2,5-dichlorobenzenediazonium is converted to the2,5-dichlorophenol, the organic acid helps to reduce plugging of thedistillation apparatus during distillation.

(5) Where the overall process also includes a step in which1,4-dichloronitrobenzene is reduced to 2,5-dichloroaniline, the organicacid can be used in the reducing step allowing for the direct transferof the reaction mixture comprising the 2,5-chloroaniline into thediazotization reactor.

(6) Where the overall process also includes both a reducing step and ahydroxylation step as discussed above, the organic acid can be recoveredfrom the hydroxylation step and recycled back to the reducing step.

Although primarily illustrated throughout this application with respectto 2,5-dichloroaniline, the improved process can be used to diazotizeother 2,5-dichloroaniline compounds that are further substituted at the3-position of the ring.

Accordingly, in one embodiment, the present disclosure relates to aprocess for the preparation of a compound corresponding in structure toFormula (IV):

or a salt thereof, the process comprising contacting a compoundcorresponding in structure to Formula (III):

or a salt thereof, with a diazotizing agent in a reaction mediumcomprising sulfuric acid and an organic acid selected from the groupconsisting of C₂-C₆-alkanoic acids and halo-C₁-C₆-alkanoic acids togenerate a diazonium product mixture comprising the compound or salt ofFormula (IV);

wherein:

R¹ is selected from the group consisting of hydrogen, halogen, cyano,—CH₃, —CH₂OH, —C(O)R², —C(O)OR³, and —B(R⁴)₂;

R² is selected from the group consisting of hydrogen, C₁-C₆-alkyl, and—NR^(A)R^(B); wherein R^(A) and R^(B) are independently selected fromthe group consisting of hydrogen and C₁-C₆-alkyl; and

R³ is selected from the group consisting of hydrogen and C₁-C₆-alkyl;and

R⁴ is selected from the group consisting of hydroxy and C₁-C₆-alkyl.

In one aspect, R¹ is hydrogen (i.e., the compound of Formula (III) is2,5-dichloroanaline). In another aspect, R¹ is selected from the groupconsisting of halogen, cyano, —CH₃, —CH₂OH, —C(O)R², —C(O)OR³, and—B(R⁴)₂; and R², R³, and R⁴ are as defined above (i.e., the compound ofFormula (III) is a 2,5-dichloroanaline compound that is furthersubstituted at the 3-position of the ring).

In one embodiment, the present disclosure relates to a process for thepreparation of a compound corresponding in structure Formula (IV):

or a salt thereof, the process comprising:

forming a reaction medium comprising sulfuric acid; an organic acidselected from the group consisting of C₂-C₆-alkanoic acids andhalo-C₁-C₆-alkanoic acids; and, optionally, a first amount of a compoundcorresponding in structure to Formula (III):

or a salt thereof; and

introducing into the reaction medium a second amount of the compound orsalt of the compound of Formula (III), and a diazotizing agent, togenerate a diazonium product mixture comprising the compound or salt ofFormula (IV);

wherein:

R¹ is selected from the group consisting of hydrogen, halogen, cyano,—CH₃, —CH₂OH, —C(O)R², —C(O)OR³, and —B(R⁴)₂;

R² is selected from the group consisting of hydrogen, C₁-C₆-alkyl, and—NR^(A)R^(B); wherein R^(A) and R^(B) are independently selected fromthe group consisting of hydrogen and C₁-C₆-alkyl; and

R³ is selected from the group consisting of hydrogen and C₁-C₆-alkyl;and

R⁴ is selected from the group consisting of hydroxy and C₁-C₆-alkyl.

In one aspect, R¹ is hydrogen (i.e., the compound of Formula (III) is2,5-dichloroanaline). In another aspect, R¹ is selected from the groupconsisting of halogen, cyano, —CH₃, —CH₂OH, —C(O)R², —C(O)OR³, and—B(R⁴)₂; and R², R³, and R⁴ are as defined above (i.e., the compound ofFormula (III) is a 2,5-dichloroanaline compound that is furthersubstituted at the 3-position of the ring).

In one embodiment, the present disclosure relates to a process for thepreparation of a compound corresponding in structure to Formula (IV):

or a salt thereof, the process comprising:

forming a reaction medium comprising sulfuric acid; an organic acidselected from the group consisting of C₂-C₆-alkanoic acids andhalo-C₁-C₆-alkanoic acids; and a compound corresponding in structure toFormula (III):

or a salt thereof; and

introducing into the reaction medium a diazotizing agent to generate adiazonium product mixture comprising the compound or salt of Formula(IV);

wherein:

R¹ is selected from the group consisting of hydrogen, halogen, cyano,—CH₃, —CH₂OH, —C(O)R², —C(O)OR³, and —B(R⁴)₂;

R² is selected from the group consisting of hydrogen, C₁-C₆-alkyl, and—NR^(A)R^(B); wherein R^(A) and R^(B) are independently selected fromthe group consisting of hydrogen and C₁-C₆-alkyl; and

R³ is selected from the group consisting of hydrogen and C₁-C₆-alkyl;and

R⁴ is selected from the group consisting of hydroxy and C₁-C₆-alkyl.

In one aspect, R¹ is hydrogen (i.e., the compound of Formula (III) is2,5-dichloroanaline). In another aspect, R¹ is selected from the groupconsisting of halogen, cyano, —CH₃, —CH₂OH, —C(O)R², —C(O)OR³, and—B(R⁴)₂; and R², R³, and R⁴ are as defined above (i.e., the compound ofFormula (III) is a 2,5-dichloroanaline compound that is furthersubstituted at the 3-position of the ring).

Scheme 3 below provides an illustration of the overall reaction when theCompound of Formula (III) is 2,5-dichloroaniline and the organic acid isacetic acid:

In general, a reaction medium comprising sulfuric acid 1,2,5-dichloroaniline 7, and acetic acid 8 is prepared. As needed, thereaction medium is cooled to a suitable temperature (e.g., from about 0°C. to about 25° C.). Under such conditions, the reaction mediumtypically will be a slurry comprising 2,5-dichloroaniline 7 and itssulfate salt 9.

Sodium nitrite 2 is added to the reaction medium (e.g., subsurfaceaddition of an aqueous solution of sodium nitrite 2). The addition ofsodium nitrite 2 to the reaction medium generates nitrosylsulfuric acid5 which then reacts with 2,5-dichloroaniline 7 to provide2,5-dichlorobenzenediazonium salt 10. The diazotization reactionproceeds quickly and substantially all of 2,5-dichloroaniline 7 reactsand is converted to 2,5-dichlorobenzenediazonium salt 10. As previouslynoted, 2,5-dichloroaniline 7 (not the sulfate salt of2,5-dichloroaniline 9) serves as the nucleophile and reacts withnitrosylsulfuric acid 5 which serves as the electrophile. Acetic acid 8functions as a co-solvent to improve solubility of 2,5-dichloroaniline 7and its sulfate salt 9 in the reaction medium enabling full conversionto 2,5-dichlorobenzenediazonium salt 10. Similarly, acetic acid 8functions as a co-solvent to improve solubility of2,5-dichlorobenzenediazonium salt 10 in the reaction medium andeffectively solubilizes that product as it is generated.

2,5-Dichlorobenzenediazonium 10 can be converted to 2,5-dichlorophenol11 in a subsequent step as shown in Scheme 3. Water 6 can serve as anucleophile, for example, and react with 2,5-dichlorobenzenediazoniumsalt 10 to provide 2,5-dichlorophenol 11, nitrogen gas 12, and sulfuricacid 1. Because diazonium salts frequently are unstable,2,5-dichlorobenzenediazonium salt 10 generally is not isolated from thereaction medium prior to conversion to 2,5-dichlorophenol 11.

A. Diazotization Reaction Medium

The organic acid employed as a co-solvent with the sulfuric acid in thepreparation of the reaction medium generally is one that does not reactwith sulfuric acid and that solubilizes the compound or salt of Formula(III). In one embodiment, the organic acid is selected from the groupconsisting of C₂-C₆-alkanoic acids and halo-C₁-C₆-alkanoic acids. In oneaspect, the organic acid is a C₂-C₆-alkanoic acid. In another aspect,the organic acid is a halo-C₁-C₆-alkanoic acid. In another aspect, theorganic acid is selected from the group consisting of acetic acid andtrifluoroacetic acid. In another aspect, the organic acid is aceticacid. In another aspect, the organic acid is trifluoroacetic acid. Inanother aspect, the reaction medium further comprises water.

i. Initial Medium Comprises Compound of Formula (III)

In certain embodiments, the initial reaction medium comprises the entireamount, or substantially the entire amount, of the compound or salt ofFormula (III) to be charged to the process. This reaction medium can beprepared in any suitable manner prior to the introduction of thediazotizing agent. In one embodiment, for example, the reaction mediumis prepared by: (i) forming a first mixture comprising the organic acidand the compound or salt of Formula (III); and (ii) adding the sulfuricacid to the first mixture to form the reaction medium. In anotherembodiment, the reaction medium is prepared by: (i) forming a firstmixture comprising the sulfuric acid and the compound or salt of Formula(III); and adding the organic acid to the first mixture to form thereaction medium. In another embodiment, the reaction medium is preparedby: (i) forming a first mixture comprising the sulfuric acid and theorganic acid; and (ii) adding the first mixture to the compound or saltof Formula (III) to form the reaction medium. In one aspect,concentrated sulfuric acid (e.g., about 98 weight percent sulfuric acid)is used in the preparation of the reaction medium. In another aspect, anaqueous solution of sulfuric acid (e.g., about 75 weight percentsulfuric acid or greater) is used in the preparation of the reactionmedium. In another aspect, glacial acetic acid is used in thepreparation of the reaction medium. In another aspect, an aqueoussolution of acetic acid (e.g., about 75 weight percent acetic acid orgreater) is used in the preparation of the reaction medium.

The reaction medium generally will comprise from about 1 molarequivalent to about 33 molar equivalents of the organic acid per mole ofthe compound or salt of Formula (III). In one embodiment, the reactionmedium comprises from about 5 molar equivalents to about 33 molarequivalents of the organic acid per mole of the compound or salt ofFormula (III). In one aspect, the reaction medium comprises from about 6molar equivalents to about 18 molar equivalents of the organic acid permole of the compound or salt of Formula (III). In another aspect, thereaction medium comprises at least about 7 molar equivalents of theorganic acid per mole of the compound or salt of Formula (III). Inanother aspect, the reaction medium comprises from about 7 molarequivalents to about 9 molar equivalents of the organic acid per mole ofthe compound or salt of Formula (III).

The reaction medium also generally comprises from about 1 molarequivalent to about 11 molar equivalents of the sulfuric acid per moleof the compound or salt of Formula (III). In one embodiment, thereaction medium comprises at least about 2 molar equivalents of thesulfuric acid per mole of the compound or salt of Formula (III). In oneaspect, the reaction medium comprises from about 2 molar equivalents toabout 8 molar equivalents of the sulfuric acid per mole of the compoundor salt of Formula (III). In another aspect, the reaction mediumcomprises from about 2 molar equivalents to about 6 molar equivalents ofthe sulfuric acid per mole of the compound or salt of Formula (III). Inanother aspect, the reaction medium comprises from about 2 molarequivalents to about 4 molar equivalents of the sulfuric acid per moleof the compound or salt of Formula (III). In another aspect, thereaction medium comprises about 2.5 moles of the organic acid per moleof the sulfuric acid.

In one embodiment, the molar ratio of the organic acid to the sulfuricacid in the reaction medium is from about 30:1 to about 1:10. In oneaspect, the molar ratio of the organic acid to the sulfuric acid is fromabout 10:1 to about 1:2. In another aspect, the molar ratio of theorganic acid to the sulfuric acid is from about 4:1 to about 1:1.

The reaction medium generally will comprise about 0.1 moles/L to about2.0 moles/L of the compound or salt of Formula (III). In one embodiment,the reaction medium comprises about 0.2 moles/L to about 1.7 moles/L ofthe compound or salt of Formula (III). In one aspect, the reactionmedium comprises about 0.3 moles/L to about 1.5 moles/L of the compoundor salt of Formula (III). In another aspect, the reaction mediumcomprises about 0.4 moles/L to about 1.3 moles/L of the compound or saltof Formula (III).

In one illustrative embodiment:

the reaction medium comprises at least about 7 molar equivalents of theorganic acid per mole of the compound or salt of Formula (III);

the reaction medium comprises at least about 2.5 molar equivalents ofthe sulfuric acid per mole of the compound or salt of Formula (III); and

the reaction medium comprises at least about 2.5 moles of the organicacid per mole of the sulfuric acid.

In another illustrative embodiment:

the reaction medium comprises from about 7 molar equivalents to about 9molar equivalents of the organic acid per mole of the compound or saltof Formula (III);

the reaction medium comprises from about 2 molar equivalents to about 4molar equivalents of the sulfuric acid per mole of the compound or saltof Formula (III); and

the reaction medium comprises about 0.4 moles/L to about 1.3 moles/L ofthe compound or salt of Formula (III).

In another illustrative embodiment:

the reaction medium comprises from about 7 molar equivalents to about 9molar equivalents of the organic acid per mole of the compound or saltof Formula (III);

the reaction medium comprises from about 2 molar equivalents to about 4molar equivalents of the sulfuric acid per mole of the compound or saltof Formula (III); and

the molar ratio of the organic acid to the sulfuric acid is from about4:1 to about 1:1.

ii. Compound of Formula (III) Added to Initial Medium

In alternative embodiments, at least a portion, substantially the entireamount, or the entire amount of the compound or salt of Formula (III) isadded to the reaction medium during the course of the process ratherthan the entire amount being present in the initial reaction mediumprior to the introduction of the diazotizing agent. In such embodiments,the initial reaction medium (i.e., the reaction medium prior to theintroduction of the diazotizing agent) may comprise sulfuric acid alone(i.e., in the absence of the organic acid), the organic acid alone(i.e., in the absence of sulfuric acid), or a combination of sulfuricacid and the organic acid, with any additional amounts of sulfuric acidand/or the organic acid for the reaction medium being introduced withthe compound or salt of Formula (III) (e.g., a solution comprising thecompound or salt of Formula (III) and the organic acid) or thediazotizing agent (e.g., a solution comprising the diazotizing agent andsulfuric acid). In one aspect, the initial reaction medium comprisessulfuric acid in the absence of the organic acid. In another aspect, theinitial reaction medium comprises the organic acid in the absence ofsulfuric acid. In another aspect, the initial reaction medium comprisessulfuric acid and the organic acid.

When a portion, substantially the entire amount, or the entire amount ofthe compound or salt of Formula (III) is added to the reaction mediumduring the course of the process, substantially the same amounts,ratios, and concentrations that were described above for the reagentsand reaction medium are applicable, but should be interpreted to reflectthe total amount of the component charged to the reaction medium overthe course of the process (e.g., the amount of the compound or salt ofFormula (III) present in the initial reaction medium plus the amount ofthe compound or salt of Formula (III) added to the reaction mediumduring the course of the process) rather than just the amount of thecomponent initially present in the reaction medium prior to theintroduction of the diazotizing agent. Example 15 below provides anexample of this approach.

In one embodiment, the compound or salt of Formula (III) is added to thereaction medium with the diazotizing agent. In one aspect, the compoundor salt of Formula (III) and the diazotizing agent are added separatelyto the reaction medium with the diazotizing agent introduced throughsubsurface addition. The compound or salt of Formula (III) and thediazotizing agent generally are added to the reaction mediumconcurrently and/or in a manner that substantially avoids generating asignificant excess of either of those reagents in the reaction medium.In one aspect, the compound or salt of Formula (III) and the diazotizingagent are added to the reaction medium concurrently. In another aspect,the compound or salt of Formula (III) and the diazotizing agent areadded to the reaction medium in a manner that substantially avoidsgenerating a significant excess of either of those reagents in thereaction medium. In another aspect, the compound or salt of Formula(III) and the diazotizing agent are added to the reaction mediumconcurrently and in a manner that substantially avoids generating asignificant excess of either of those reagents in the reaction medium.In another aspect, the rate of addition of each reagent is controlled tomaintain a molar ratio of about 1:1 during the addition. Avoiding anexcess of either reagent in the reaction medium during the addition canhelp to maintain a low viscosity reaction mixture, reduce reactorsolids, and/or reduce by-product formation.

In one embodiment, the process comprises concurrently introducing thediazotizing agent, the organic acid, and the compound or salt of Formula(III) into the reaction medium. In one aspect, the process comprisesconcurrently introducing the diazotizing agent and a solution comprisingthe organic acid and the compound or salt of Formula (III) into thereaction medium. In another aspect, the reaction medium initiallycomprises (i.e., comprises before the addition of any diazotizing agent)sulfuric acid in the absence of the organic acid. In another aspect, thereaction medium initially comprises sulfuric acid in the absence of thecompound or salt of Formula (III). In another aspect, the reactionmedium initially comprises sulfuric acid in the absence of the organicacid and the compound or salt of Formula (III). In another aspect, thereaction medium comprises sulfuric acid and the organic acid in theabsence of the compound or salt of Formula (III).

The compound or salt of Formula (III) used in the preparation of thereaction medium, or added to the reaction medium during the process,typically does not require fine milling and can even be added to thereaction medium as an unmilled solid. In one embodiment, the compound orsalt of Formula (III) used in the preparation of the reaction medium isprovided as a solid having a D₉₀ particle size greater than about 150microns. In another embodiment, the compound or salt of Formula (III)used in the preparation of the reaction medium is provided as anunmilled solid.

B. Diazotizing Agent

The diazotizing agent can be introduced into the reaction medium, forexample, as an alkali metal nitrite, nitrous acid, or nitrosylsulfuricacid. In one embodiment, the diazotizing agent is introduced into thereaction medium as an alkali metal nitrite, particularly sodium nitrite.In one embodiment, the diazotizing agent is selected from the groupconsisting of sodium nitrite and calcium nitrite. In another embodiment,the diazotizing agent is introduced into the reaction medium as sodiumnitrite. In another embodiment, the diazotizing agent is introduced intothe reaction medium as calcium nitrite. In another embodiment, thediazotizing agent is introduced into the reaction medium as nitrousacid. In another embodiment, the diazotizing agent is introduced intothe reaction medium as nitrosylsulfuric acid.

As previously discussed with respect to sodium nitrite, an alkali metalnitrite introduced into the reaction medium reacts with the sulfuricacid present to generate nitrous acid, the nitrous acid generated thenreacts with the sulfuric acid present to generate nitrosylsulfuric acid,and the nitrosylsulfuric acid then reacts with the compound or salt ofFormula (III) to generate the compound or salt of Formula (IV). The mainobjective is to introduce the nitrite to the reaction medium in a mannerthat results in the conversion of the nitrite to nitrous acid which canthen react with sulfuric acid to generate nitrosylsulfuric acid.

When an alkali metal nitrite is introduced into the reaction medium asthe diazotizing agent, it can be introduced in various forms. In oneembodiment, the alkali metal nitrite added to the reaction medium as asolid. Addition as a solid, however, increases the difficulty ofmaintaining a controlled and consistent addition of the nitrite.

In another embodiment, the alkali metal nitrite is added to the reactionmedium as an aqueous solution comprising the alkali metal nitrite. Inone aspect, the aqueous solution comprising the alkali metal nitrite isadded drop wise to the reaction medium. In another aspect, the aqueoussolution comprising the alkali metal nitrite is introduced into thereaction medium through subsurface addition. In another aspect, thealkali metal nitrite is selected from the group consisting of sodiumnitrite and calcium nitrite. In another aspect, alkali metal nitrite issodium nitrite. In another aspect, the alkali metal nitrite is calciumnitrite.

In another embodiment, the alkali metal nitrite is added to the reactionmedium as a solution of the alkali metal nitrite in sulfuric acid. Inone aspect, the solution of the alkali metal nitrite in sulfuric acid isadded drop wise to the reaction medium. In another aspect, the solutionof the alkali metal nitrite in sulfuric acid is introduced into thereaction medium through subsurface addition. In another aspect, thealkali metal nitrite is selected from the group consisting of sodiumnitrite and calcium nitrite. In another aspect, alkali metal nitrite issodium nitrite. In another aspect, the alkali metal nitrite is calciumnitrite.

The diazotization reaction proceeds quickly once the diazotizing agentis introduced into the reaction medium and higher temperatures are notrequired to drive the diazotization reaction to completion. In oneembodiment, the reaction medium has a temperature less than or equal toabout 25° C. when the diazotizing agent is introduced. In one aspect,the reaction medium has a temperature less than or equal to about 10° C.when the diazotizing agent is introduced. In another aspect, thereaction medium has a temperature from about 0° C. to about 25° C. whenthe diazotizing agent is introduced. In another aspect, the reactionmedium has a temperature from about 0° C. to about 20° C. when thediazotizing agent is introduced. In another aspect, the reaction mediumhas a temperature from about 0° C. to about 15° C. when the diazotizingagent is introduced. In another aspect, the reaction medium has atemperature from about 0° C. to about 10° C. when the diazotizing agentis introduced. In another aspect, the reaction medium has a temperaturefrom about 10° C. to about 25° C. when the diazotizing agent isintroduced. In another aspect, the reaction medium has a temperaturefrom about 5° C. to about 15° C. when the diazotizing agent isintroduced.

Although smaller or larger amounts of the diazotizing agent can beemployed for the diazotization reaction, a suitable amount generallywill be at least about 0.9 molar equivalents. A stoichiometric excess ofthe diazotizing agent generally will provide a better conversion of thecompound or salt of Formula (III) to the compound or salt of Formula(IV), but the stoichiometric excess need not be a large stoichiometricexcess. In one embodiment, at least a 0.9 molar equivalent amount of thediazotizing agent per mole of the compound or salt of Formula (III) isintroduced into the reaction medium. In one aspect, at least a molarequivalent amount of the diazotizing agent per mole of the compound orsalt of Formula (III) is introduced into the reaction medium. In anotheraspect, about 0.9 molar equivalents to about 1.5 molar equivalents ofthe diazotizing agent per mole of the compound or salt of Formula (III)is introduced into the reaction medium. In another aspect, about 1.0molar equivalent to about 1.5 molar equivalents of the diazotizing agentper mole of the compound or salt of Formula (III) is introduced into thereaction medium. In another aspect, about 1.0 molar equivalent to about1.2 molar equivalents of the diazotizing agent per mole of the compoundor salt of Formula (III) is introduced into the reaction medium. Inanother aspect, about 1.05 molar equivalents of the diazotizing agentper mole of the compound or salt of Formula (III) are introduced intothe reaction medium. In another aspect, about 1.05 molar equivalents ofsodium nitrite per mole of the compound or salt of Formula (III) areintroduced into the reaction medium through subsurface addition.

As previously described above, a portion, substantially the entireamount, or the entire amount of the compound or salt of Formula (III)can be added to the reaction medium during the course of the processrather than being present in the initial reaction medium prior to theintroduction of the diazotizing agent. The same process conditionsgenerally apply regardless of whether the diazotizing agent isintroduced into a reaction medium containing substantially all of thecompound or salt of Formula (III) to be charged to the process or thediazotizing agent and at least a portion of the compound or salt ofFormula (III) to be charged to the process are introduced into thereaction medium. When the compound or salt of Formula (III) is added tothe reaction medium during the course of the process, however, itgenerally is beneficial to introduce the compound or salt of Formula(III) and the diazotizing agent to the reaction medium concurrently andin a manner that avoids generating a significant excess of either ofthose reagents in the reaction medium. In one aspect, the rate ofaddition of each reagent is controlled such that about 0.9 molarequivalent to about 1.5 molar equivalents of diazotizing agent are addedper mole of the compound or salt of Formula (III) added. In anotheraspect, the rate of addition of each reagent is controlled such thatabout 1.0 molar equivalent to about 1.5 molar equivalents of thediazotizing agent are added per mole of the compound or salt of Formula(III) added. In another aspect, the rate of addition of each reagent iscontrolled such that about 1.0 molar equivalent to about 1.2 molarequivalents of the diazotizing agent are added per mole of the compoundor salt of Formula (III) added.

In another aspect, the rate of addition of each reagent is controlledsuch that about 1.0 molar equivalent to about 1.05 molar equivalents ofthe diazotizing agent are added per mole of the compound or salt ofFormula (III) added. In another aspect, the rate of addition of eachreagent is controlled such that about 1.0 molar equivalent of thediazotizing agent is added per mole of the compound or salt of Formula(III) added. In one aspect, the compound or salt of Formula (III) andthe diazotizing agent are added separately to the reaction medium withthe diazotizing agent introduced through subsurface addition.

In one embodiment, the diazotizing agent and the compound or salt ofFormula (III) are separately introduced into the reaction medium as afirst solution comprising the diazotizing agent, and a second solutioncomprising acetic acid and the compound or salt of Formula (III). In oneaspect, the first solution and the second solution are introduced intothe reaction medium in a substantially concurrent manner. In anotheraspect, the first solution is an aqueous solution comprising an alkalimetal nitrite, and the second solution comprises acetic acid and thecompound or salt of Formula (III). In another aspect, the first solutioncomprises an alkali metal nitrite and sulfuric acid, and the secondsolution comprises acetic acid and the compound or salt of Formula(III). In another aspect, the first solution comprises nitrosyl sulfuricacid, and a second solution comprises acetic acid and the compound orsalt of Formula (III).

As discussed above, the improved process provides a suitable conversionof the compound or salt of Formula (III) to the compound or salt ofFormula (IV). In one embodiment, the percent conversion of the compoundor salt of Formula (III) to the compound or salt of Formula (IV) is atleast about 80%. In one aspect, the percent conversion of the compoundor salt of Formula (III) to the compound or salt of Formula (IV) is atleast about 85%. In another aspect, the percent conversion of thecompound or salt of Formula (III) to the compound or salt of Formula(IV) is at least about 90%. In another aspect, the percent conversion ofthe compound or salt of Formula (III) to the compound or salt of Formula(IV) is at least about 95%.

C. Quenching of Diazotizing Agent

Where the diazotizing agent is an alkali metal nitrite (e.g., sodiumnitrite or calcium nitrite), nitrosylsulfuric acid, or otherwise resultsin an excess of nitrous acid being present in the medium, it can bebeneficial to add a sufficient amount of a quenching agent to thereaction mixture comprising the 2,5-dichlorobenzenediazonium in order todecompose any excess nitrous acid remaining prior to converting the2,5-dichlorobenzenediazonium to the 2,5-dichlorophenol. If excessnitrous acid is present during the hydroxylation step described below,for example, under the elevated temperatures of the hydroxylation stepthe nitrous acid can react with the 2,5-dichlorophenol generated.

In one embodiment of the present disclosure, therefore, the processfurther comprises adding a quenching agent to the diazonium productmixture in an amount sufficient to decompose any remaining diazotizingagent prior to the subsequent hydrolyzing step. In one aspect, thequenching agent is selected from the group consisting of urea andsulfamic acid. In another aspect, the quenching agent is urea. Inanother aspect, the quenching agent is sulfamic acid. The reactionpathways for decomposition of nitrous acid when the quenching agent iseither urea (1) or sulfamic acid (2) are shown in Scheme 4 below.

III. HYDROXYLATION OF 2,5-DICHLOROBENZENEDIAZONIUM

As previously noted, the 2,5-dichlorobenzenediazonium prepared asdescribed above can be hydrolyzed to provide the corresponding2,5-dichlorophenol, a key intermediate used in the manufacture ofdicamba.

Accordingly, in one embodiment, the present disclosure relates to aprocess for the preparation of a compound corresponding in structure toFormula (V):

or a salt thereof, the process comprising:

contacting a compound corresponding in structure to Formula (III):

or a salt thereof, with a diazotizing agent in a reaction mediumcomprising sulfuric acid and an organic acid selected from the groupconsisting of C₂-C₆-alkanoic acids and halo-C₁-C₆-alkanoic acids togenerate a diazonium product mixture comprising the compound or salt ofFormula (IV):

or a salt thereof; and

hydrolyzing the compound or salt of Formula (IV) to generate a phenolproduct mixture comprising the compound or salt of Formula (V);

wherein:

R¹ is selected from the group consisting of hydrogen, halogen, cyano,—CH₃, —CH₂OH, —C(O)R², —C(O)OR³, and —B(R⁴)₂;

R² is selected from the group consisting of hydrogen, C₁-C₆-alkyl, and—NR^(A)R^(B); wherein R^(A) and R^(B) are independently selected fromthe group consisting of hydrogen and C₁-C₆-alkyl; and

R³ is selected from the group consisting of hydrogen and C₁-C₆-alkyl;and

R⁴ is selected from the group consisting of hydroxy and C₁-C₆-alkyl.

In one aspect, R¹ is hydrogen (i.e., the compound of Formula (III) is2,5-dichloroanaline). In another aspect, R¹ is selected from the groupconsisting of halogen, cyano, —CH₃, —CH₂OH, —C(O)R², —C(O)OR³, and—B(R⁴)₂; and R², R³, and R⁴ are as defined above (i.e., the compound ofFormula (III) is a 2,5-dichloroanaline compound that is furthersubstituted at the 3-position of the ring).

In one embodiment, the present disclosure relates to a process for thepreparation of a compound corresponding in structure to Formula (V):

or a salt thereof, the process comprising:

forming a reaction medium comprising sulfuric acid; an organic acidselected from the group consisting of C₂-C₆-alkanoic acids andhalo-C₁-C₆-alkanoic acids; and, optionally, a first amount of a compoundcorresponding in structure to Formula (III):

or a salt thereof;

introducing into the reaction medium a second amount of the compound orsalt of the compound of Formula (III), and a diazotizing agent, togenerate a diazonium product mixture comprising the compound or salt ofFormula (IV);

or a salt thereof; and

hydrolyzing the compound or salt of Formula (IV) to generate a phenolproduct mixture comprising the compound or salt of Formula (V);

wherein:

R¹ is selected from the group consisting of hydrogen, halogen, cyano,—CH₃, —CH₂OH, —C(O)R², —C(O)OR³, and —B(R⁴)₂;

R² is selected from the group consisting of hydrogen, C₁-C₆-alkyl, and—NR^(A)R^(B); wherein R^(A) and R^(B) are independently selected fromthe group consisting of hydrogen and C₁-C₆-alkyl; and

R³ is selected from the group consisting of hydrogen and C₁-C₆-alkyl;and

R⁴ is selected from the group consisting of hydroxy and C₁-C₆-alkyl.

In one aspect, R¹ is hydrogen (i.e., the compound of Formula (III) is2,5-dichloroanaline). In another aspect, R¹ is selected from the groupconsisting of halogen, cyano, —CH₃, —CH₂OH, —C(O)R², —C(O)OR³, and—B(R⁴)₂; and R², R³, and R⁴ are as defined above (i.e., the compound ofFormula (III) is a 2,5-dichloroanaline compound that is furthersubstituted at the 3-position of the ring).

In one embodiment, the present disclosure relates to a process for thepreparation of a compound corresponding in structure to Formula (V):

or a salt thereof, the process comprising:

forming a reaction medium comprising sulfuric acid; an organic acidselected from the group consisting of C₂-C₆-alkanoic acids andhalo-C₁-C₆-alkanoic acids; and a compound corresponding in structure toFormula (III):

or a salt thereof; and

introducing into the reaction medium a diazotizing agent to generate adiazonium product mixture comprising a compound corresponding instructure to Formula (IV):

or a salt thereof; and

hydrolyzing the compound or salt of Formula (IV) to generate a phenolproduct mixture comprising the compound or salt of Formula (V);

wherein:

R¹ is selected from the group consisting of hydrogen, halogen, cyano,—CH₃, —CH₂OH, —C(O)R², —C(O)OR³, and —B(R⁴)₂;

R² is selected from the group consisting of hydrogen, C₁-C₆-alkyl, and—NR^(A)R^(B); wherein R^(A) and R^(B) are independently selected fromthe group consisting of hydrogen and C₁-C₆-alkyl; and

R³ is selected from the group consisting of hydrogen and C₁-C₆-alkyl;and

R⁴ is selected from the group consisting of hydroxy and C₁-C₆-alkyl.

In one aspect, R¹ is hydrogen (i.e., the compound of Formula (III) is2,5-dichloroanaline). In another aspect, R¹ is selected from the groupconsisting of halogen, cyano, —CH₃, —CH₂OH, —C(O)R², —C(O)OR³, and—B(R⁴)₂; and R², R³, and R⁴ are as defined above (i.e., the compound ofFormula (III) is a 2,5-dichloroanaline compound that is furthersubstituted at the 3-position of the ring).

In one embodiment, the process further comprises adding a quenchingagent to the diazonium product mixture in an amount sufficient todecompose any remaining diazotizing agent prior to the hydrolyzing step.

In one embodiment, the process further comprises isolating the compoundor salt of Formula (V) from the phenol product mixture.

In one embodiment, the process further comprises recovering the organicacid from the hydrolyzing step and recycling the recovered organic acidto a prior process step.

In one embodiment, the process further comprises recovering the sulfuricacid from the hydrolyzing step and recycling the recovered sulfuric acidto the diazotization and/or hydrolysis process step(s). In one aspect,the recovered sulfuric acid is used to prepare the reaction medium intowhich the diazotizing agent is introduced to generate the diazoniumproduct mixture comprising the compound or salt of Formula (IV).

In one embodiment, the process further comprises (a) recovering theorganic acid from the hydrolyzing step and recycling the recoveredorganic acid to a prior process step; and (b) recovering the sulfuricacid from the hydrolyzing step and recycling the recovered sulfuric acidto the diazotization and/or hydrolysis process step(s). In one aspect,the recovered sulfuric acid is used to prepare the reaction medium intowhich the diazotizing agent is introduced to generate the diazoniumproduct mixture comprising the compound or salt of Formula (IV).

Although the compound or salt of Formula (IV) can be isolated from thediazonium product mixture and then hydrolyzed to the compound or salt ofFormula (V), such isolation typically is not carried out prior to thehydrolyzing step. In view of the potential instability of isolateddiazonium salts, the compound or salt of Formula (IV) generally ishydrolyzed to the compound or salt of Formula (V) in situ in thediazonium product mixture and the compound or salt of Formula (V)recovered from the resulting phenol product mixture.

The compound or salt of Formula (IV) can be hydrolyzed to the compoundor salt of Formula (V) through any suitable means. In one embodiment,for example, the compound or salt of Formula (IV) is hydrolyzed byheating the diazonium product mixture to generate a phenol productmixture comprising the compound or salt of Formula (V). In one aspect,the compound or salt of Formula (IV) is subjected to thermal hydrolysisand the resulting compound or salt of Formula (V) is immediatelyisolated from the remaining diazonium (e.g., through azeotropic steamdistillation or extraction into an organic phase present in the reactor)to minimize further reaction between the compound or salt of Formula (V)and the remaining diazonium.

In another embodiment, the compound or salt of Formula (IV) ishydrolyzed by subjecting the diazonium product mixture to steamdistillation to generate a phenol product mixture comprising thecompound or salt of Formula (V). In one aspect, the diazonium productmixture is maintained at a temperature between about 105° C. to about200° C. during the steam distillation. In another aspect, the diazoniumproduct mixture is maintained at a temperature between about 130° C. toabout 170° C. during the steam distillation. In another aspect, thediazonium product mixture is maintained at a temperature of about 150°C. during the steam distillation. In another aspect, the phenol productmixture resulting from the steam distillation is a distillate comprisingthe organic acid, water, and the compound or salt of Formula (V). Inanother aspect, the process further comprises isolating the compound orsalt of Formula (V) from the distillate. In another aspect, the processfurther comprises recovering the organic acid from the distillate andrecycling the recovered organic acid to a prior process step.

By way of further illustration, Example 12 below describes thesubsurface addition of the diazonium product mixture to hot concentratedsulfuric acid using a syringe pump followed by the introduction of steaminto the resulting mixture at a rate sufficient to provide for theazeotropic distillation of the 2,5-dichlorophenol. Although the additionof steam to the sulfuric acid generated an initial exotherm, additionalheating (a heating mantle) was supplied as required to maintain theresulting mixture at a temperature of about 150° C. during the steamdistillation. The overall yield of the 2,5-dichlorophenol was around90%.

In another embodiment, the compound or salt of Formula (IV) ishydrolyzed by: (i) combining the diazonium product mixture with anorganic solvent to form a biphasic mixture comprising the compound orsalt of Formula (IV); and (ii) heating the biphasic mixture to generatea phenol product mixture comprising the compound or salt of Formula (V).In one aspect, the organic solvent comprises one or more xylenes. Inanother aspect, the biphasic mixture is heated under reflux conditions.In another aspect, the biphasic mixture is refluxed at a temperaturefrom about 95° C. to about 125° C. In another aspect, the biphasicmixture is refluxed at a temperature from about 95° C. to about 125° C.for a period of about 30 minutes to about 500 minutes.

The biphasic mixture upon cooling after refluxing comprises an aqueousphase and an organic phase comprising the compound or salt of Formula(V). The organic phase can be separated from the aqueous phase byconventional means (such as phase separation) to provide a phenolproduct mixture comprising the compound or salt of Formula (V). Thecompound or salt of Formula (V) then can be isolated from the phenolproduct mixture by conventional means (such as evaporation ordistillation).

Alternatively, water (e.g., deionized water, etc.) can be used in placeof steam to hydrolyze the compound or salt of Formula (V) present in thediazonium product mixture in a manner similar to the various embodimentsdescribed above. The water likewise serves as a nucleophile in thehydrolysis reaction and also promotes the azeotropic distillation of thehydrolysis product. Use of water instead of steam potentially can reduceprocess costs and problems associated with the use of glass-linedequipment. The entire amounts of the diazonium product mixture and watercan be charged to a hydrolysis reactor (such as a distillation column,etc.) containing a reaction medium comprising aqueous sulfuric acid atthe beginning of the hydrolysis step or, alternatively, at least aportion of the diazonium product mixture and a portion of the water canbe added to the reaction medium during the course of the hydrolysisstep.

In one embodiment, at least a portion of the diazonium product mixtureand a portion of the water are introduced concurrently into the reactionmedium comprising aqueous sulfuric acid over a period of time. Duringthis addition, the resulting reaction medium is maintained at atemperature sufficient to hydrolyze the compound or salt of Formula(III) to the compound or salt of Formula (IV) and achieve the azeotropicdistillation of the compound or salt of Formula (IV) from the reactionmedium. Suitable distillation conditions are as previously describedabove. In one aspect, the reaction medium is maintained at a temperatureof at least about 150° C. and the additions of the diazonium productmixture and the water to the reaction medium are completed inapproximately the same period of time. In another aspect, the reactionmedium is maintained at a temperature of about 160° C. Example 16 belowprovides an example of the concurrent addition of the diazonium productmixture and water to the reaction medium.

In another embodiment, water is added to the reaction medium before thediazonium product mixture is introduced to the reaction medium and,optionally, again after the diazonium product mixture addition to thereaction medium has been completed. In this embodiment, a reactionmedium comprising aqueous sulfuric acid is placed in a hydrolysisreactor (such as a distillation column, etc.) and heated. The reactionmedium can comprise, for example, a commercially available aqueoussulfuric acid solution, aqueous sulfuric acid recycled from a laterstage of the process, or aqueous sulfuric acid prepared from aconcentrated sulfuric acid solution (such as by adding the first portionof water to the concentrated sulfuric acid, either before or after theplacing the concentrated sulfuric acid in the hydrolysis reactor). Thereaction medium is heated to a temperature sufficient to provide for asubstantially constant distillation of water in the distillation bridge.A second portion of water and the diazonium product mixture are thenconcurrently introduced to the reaction medium over a period of time.During this addition, the resulting reaction medium is maintained at atemperature sufficient to hydrolyze the compound or salt of Formula(III) to the compound or salt of Formula (IV) and achieve the azeotropicdistillation of the compound or salt of Formula (IV) from the reactionmedium. Suitable distillation conditions are as previously describedabove. Once the addition of the diazonium product mixture is complete, athird portion of water is optionally introduced into the reaction mediumand heating is discontinued. In one aspect, the reaction medium ismaintained at a temperature of at least about 150° C. and/or thedistilling head is maintained at a temperature of at least about 85° C.In another aspect, the reaction medium is maintained at a temperature ofabout 160° C. and/or the distilling head is maintained at a temperatureof about 90° C. Example 16 below provides an example of this approach.

IV. RECYCLING OF ORGANIC ACID

As mentioned above, the process may further comprise recovering theorganic acid from the hydrolyzing step and recycling the recoveredorganic acid to a prior process step.

V. RECYCLING OF SULFURIC ACID

As mentioned above, the process may further comprise recovering thesulfuric acid from the hydrolyzing step and recycling the recoveredsulfuric acid to a prior process step. For example, the process canfurther comprise recovering sulfuric acid from the hydrolyzing step andrecycling the recovered sulfuric acid to the diazotization and/orhydrolysis process step(s). In one aspect, the recovered sulfuric acidis used to prepare the reaction medium into which the diazotizing agentis introduced to generate the diazonium product mixture comprising thecompound or salt of Formula (IV). In another aspect, the recoveredsulfuric acid is used to prepare the reaction medium into which thediazonium product mixture is hydrolyzed to generate a phenol productmixture comprising the compound or salt of Formula (V). Such recyclingcan reduce the sulfuric acid requirements of, and costs associated with,the process.

VI. REDUCTION OF THE COMPOUND OF FORMULA (II)

In one embodiment, the process further comprises the step of reducing acompound corresponding in structure to Formula (II):

or a salt thereof, to generate a compound corresponding in structure toFormula (III):

or a salt thereof.

wherein:

R¹ is selected from the group consisting of hydrogen, halogen, cyano,—CH₃, —CH₂OH, —C(O)R², —C(O)OR³, and —B(R⁴)₂;

R² is selected from the group consisting of hydrogen, C₁-C₆-alkyl, and—NR^(A)R^(B); wherein R^(A) and R^(B) are independently selected fromthe group consisting of hydrogen and C₁-C₆-alkyl; and

R³ is selected from the group consisting of hydrogen and C₁-C₆-alkyl;and

R⁴ is selected from the group consisting of hydroxy and C₁-C₆-alkyl.

In one aspect, R¹ is hydrogen (i.e., the compound of Formula (II) is1,4-dichloronitrobenzene). In another aspect, R¹ is selected from thegroup consisting of halogen, cyano, —CH₃, —CH₂OH, —C(O)R², —C(O)OR³, and—B(R⁴)₂; and R², R³, and R⁴ are as defined above (i.e., the compound ofFormula (II) is a 1,4-dichloronitrobenzene compound that is furthersubstituted at the 3-position of the ring).

The reducing step can be carried out in any suitable manner such as, forexample, contacting the compound or salt of Formula (II) with hydrogenin the presence of a suitable catalyst to generate the compound or saltof Formula (III). In one aspect, the reducing step is conducted in asolvent comprising the same organic acid that is used in the diazotizingstep. In another aspect, the reducing step is conducted in a solventcomprising the same organic acid that is used in the diazotizing step,and the process comprises recovering the organic acid from thehydrolyzing step and recycling the recovered organic acid to thereducing step.

In one illustrative embodiment, the process further comprises a reducingstep in which 1,4-dichloronitrobenzene is converted to 2,5-chloroanilineas shown in Scheme 5 below.

It has been discovered that the reducing step can be conducted in aceticacid without unwanted dechlorination of the 2,5-dichloroaniline productoccurring. Upon completion of hydrogenation of the1,4-dichloronitrobenzene, the acetic acid reaction mixture comprisingthe resulting 2,5-dichloroaniline can be directly transferred into thediazonium reactor. The direct transfer eliminates the need to isolateand purify the 2,4-dichloroaniline and the related solvent and equipmentrequirements. During the diazotizing step, this procedure avoids the useof a mill to assist with the solubility of 2,5-dichloroaniline andreduces the amount of sulfuric acid needed during the course of thereaction. An additional benefit of using the acetic acid is realizedduring the later distillation purification of 2,5-dichlorophenol inwhich the acetic acid prevents plugging of the distillation apparatus.The acetic acid additionally can be recovered and recycled back into theprocess simplifying the overall synthetic sequence and reducing waste.

VII. CONVERSION OF 2,5-DICHLOROPHENOL TO DICAMBA

As previously noted, the 2,5-dichlorophenol prepared as described aboveis a key intermediate used in the manufacture of dicamba. A number ofsynthetic routes for converting 2,5-dichlorophenol to dicamba have beenreported in the literature and any such suitable route may be employed.For example, many of the reported routes generally involve the followingprocess steps: (i) carboxylating the 2,5-dichlorophenol to provide2-hydroxy-3,6-dichloro-benzoic acid (e.g., carboxylation using aKolbe-Schmidtt Reaction), (ii) methylating the2-hydroxy-3,6-dichloro-benzoic acid to provide methyl3,6-dichloro-2-methoxybenzoate (e.g., methylation by treatment withdimethyl sulfate, dimethyl carbonate, or methyl chloride), and (iii)selectively demethylating the ester group of the methyl3,6-dichloro-2-methoxybenzoate to provide dicamba (e.g., saponification)as shown in Scheme 6 below:

Among the various literature references reporting synthetic methods forpreparing dicamba or dicamba intermediates, for example, are thefollowing:

-   (1) U.S. Pat. No. 3,013,054 reports a process for preparing dicamba    that proceeds through a 2,5-dichlorophenol intermediate.-   (2) Zhang, et al., “Synthesis of Herbicide Dicamba,” Nongyao 2002,    41 (11), 13-14 (Ch.), reports a process for the preparation of    dicamba from 2-5-dichloroaniline that proceeds through a    2,5-dichlorophenol intermediate.-   (3) Zhang, et al., “Study on the Preparation of Dicamba,” Nongyao    2002, 41 (7), 15-17 (Ch.), reports a three-step process for the    preparation of dicamba from 2,5-dichlorophenol.-   (4) Eckstein, et al., Przem. Chem. 1979, 58 (10), 533-536 (Pol.),    reports a process for preparing dicamba from a 2,5-dichlorophenol    sodium salt.-   (5) U.S. Pat. No. 3,345,157 reports a process for methylating    2-hydroxy-3,6-dichloro-benzoic acid to provide dicamba.-   (6) Matyakh, et al., “2-Methoxy-3,6-dichloro-benzoic acid,”    Otkrytiya, Izobret. Prom. Obraztsy, Tovarnye, Znake 1973, 50 (18),    177-178, reports a process for methylating a    2-hydroxy-3,6-dichloro-benzoic acid sodium salt to provide dicamba.-   (7) Zhang, et al., “Study on the 0-Alkylation for    3,6-dichlorosalicylic Acid by Chloromethane,” Huangong Shikan 2002,    16 (12) 45-48 (Ch.), reports the O-alkylation of    2-hydroxy-3,6-dichloro-benzoic acid to provide dicamba.-   (8) CN102942474A report a process via carboxylation of    2,5-dichlorophenol and methylation of 3,6-dichlorosalicylic acid    with chloromethane to provide dicamba.-   (9) CN102125035B reports a process involving carboxylation of    2,5-dichlorophenol and methylation of 3,6-dichlorosalicylic acid    with dimethyl carbonate to provide dicamba.-   (10) CN1830942A reports a process involving methylation of    3,6-dichlorosalicylic acid with dimethyl sulfate to provide dicamba.

Accordingly, in one embodiment, the present disclosure relates to aprocess for the preparation of dicamba, i.e., a compound correspondingin structure to Formula (VI):

or a salt thereof, wherein the process comprises converting a compoundprepared as disclosed in this specification and corresponding instructure to Formula (V-a):

or a salt thereof, to the compound of Formula (VI).

In one embodiment, the present disclosure relates to a process for thepreparation of dicamba, i.e., a compound corresponding in structure toFormula (VI):

or a salt thereof, the process comprising:

contacting a compound corresponding in structure to Formula (III-a):

or a salt thereof, with a diazotizing agent in a reaction mediumcomprising sulfuric acid and an organic acid selected from the groupconsisting of C₂-C₆-alkanoic acids and halo-C₁-C₆-alkanoic acids togenerate a diazonium product mixture comprising a compound correspondingin structure to Formula (IV-a):

or a salt thereof;

hydrolyzing the compound or salt of Formula (IV-a) to generate a phenolproduct mixture comprising a compound corresponding in structure toFormula (V-a):

or a salt thereof;

carboxylating the compound or salt of Formula (V-a) to generate acarboxylated product mixture comprising a compound corresponding instructure to Formula (V-b):

or a salt thereof; and

converting the compound or salt of Formula (V-b) to the compound or saltof Formula (VI).

In one aspect, the converting step comprises methylating the compound orsalt of Formula (V-b) to generate a methylated product mixturecomprising a compound corresponding in structure to Formula (V-c):

or a salt thereof; and selectively demethylating the compound or salt ofFormula (V-c) to generate a dicamba product mixture comprising thecompound or salt of Formula (VI). In another aspect, the converting stepcomprises selectively methylating the compound or salt of Formula (V-b)to generate a dicamba product mixture comprising the compound or salt ofFormula (VI).

In one embodiment, the present disclosure relates to a process for thepreparation of dicamba, i.e., a compound corresponding in structure toFormula (VI):

or a salt thereof, the process comprising:

or a salt thereof, the process comprising:

forming a reaction medium comprising sulfuric acid; an organic acidselected from the group consisting of C₂-C₆-alkanoic acids andhalo-C₁-C₆-alkanoic acids; and, optionally, a first amount of a compoundcorresponding in structure to Formula (III-a):

or a salt thereof;

introducing into the reaction medium a second amount of the compound orsalt of the compound of Formula (III), and a diazotizing agent, togenerate a diazonium product mixture comprising a compound correspondingin structure to Formula (IV-a):

or a salt thereof;

hydrolyzing the compound or salt of Formula (IV-a) to generate a phenolproduct mixture comprising a compound corresponding in structure toFormula (V-a):

or a salt thereof; and

carboxylating the compound or salt of Formula (V-a) to generate acarboxylated product mixture comprising a compound corresponding instructure to Formula (V-b):

or a salt thereof; and

converting the compound or salt of Formula (V-b) to the compound or saltof Formula (VI).

In one aspect, the converting step comprises methylating the compound orsalt of Formula (V-b) to generate a methylated product mixturecomprising a compound corresponding in structure to Formula (V-c):

or a salt thereof; and selectively demethylating the compound or salt ofFormula (V-c) to generate a dicamba product mixture comprising thecompound or salt of Formula (VI). In another aspect, the converting stepcomprises selectively methylating the compound or salt of Formula (V-b)to generate a dicamba product mixture comprising the compound or salt ofFormula (VI).

In one embodiment, the present disclosure relates to a process for thepreparation of dicamba, i.e., a compound corresponding in structure toFormula (VI):

or a salt thereof, the process comprising:

forming a reaction medium comprising sulfuric acid; an organic acidselected from the group consisting of C₂-C₆-alkanoic acids andhalo-C₁-C₆-alkanoic acids; and a compound corresponding in structure toFormula (III-a):

or a salt thereof;

introducing into the reaction medium a diazotizing agent to generate adiazonium product mixture comprising a compound corresponding instructure to Formula (IV-a):

or a salt thereof;

hydrolyzing the compound or salt of Formula (IV-a) to generate a phenolproduct mixture comprising a compound corresponding in structure toFormula (V-a):

or a salt thereof;

carboxylating the compound or salt of Formula (V-a) to generate acarboxylated product mixture comprising a compound corresponding instructure to Formula (V-b):

or a salt thereof; and

converting the compound or salt of Formula (V-b) to the compound or saltof Formula (VI).

In one aspect, the converting step comprises methylating the compound orsalt of Formula (V-b) to generate a methylated product mixturecomprising a compound corresponding in structure to Formula (V-c):

or a salt thereof; and selectively demethylating the compound or salt ofFormula (V-c) to generate a dicamba product mixture comprising thecompound or salt of Formula (VI). In another aspect, the converting stepcomprises selectively methylating the compound or salt of Formula (V-b)to generate a dicamba product mixture comprising the compound or salt ofFormula (VI).

In one embodiment, the process further comprises isolating the compoundor salt of Formula (VI) from the dicamba product mixture.

VIII. EXAMPLES Example 1 Analytical Methods (2,5-Dichloroaniline and2,5-Dichlorophenol)

Unless otherwise stated, chromatography was used to monitor the2,5-dichloroaniline consumed and the 2,5-dichlorophenol produced in thediazotization/hydroxylation reactions discussed in the followingexamples:

Additional analytical methods used in certain of the examples also arediscussed below.

A. Thin Layer Chromatography (TLC) Method

In one analytical method, thin layer chromatography (TLC) was used tomonitor the reaction. For example, TLC using a mobile phase ofdichloromethane, hexane, and methanol in a ratio of 20 to 75 to 5,respectively, gave a retention factor for 2,5-dichloroaniline of about0.5 and a retention factor for 2,5-dichlorophenol of about 0.3.2,5-Dichlorophenol exhibited a yellow spot when developed with potassiumpermanganate stain. 2,5-Dichloroaniline exhibited a blue spot whendeveloped with cerium-ammonium-molybdate (CAM) stain.2,5-Dichlorobenzene diazonium, however, stayed at the baseline of theplate. Disappearance of the 2,5-dichloroaniline spot on TLC generallyindicated that the 2,5-dichloroaniline had been converted to the2,5-dichlorobenzene diazonium.

B. HPLC Method

In another analytical method, HPLC was used to monitor the reaction.HPLC was conducted on an Agilent 1260 Infinity Analytical-Scale LC/MSPurification System equipped with a diode array UV detector andmonitored at 280 nm. The column was an Agilent Poroshell 120 C-18EC,4.6×50 mm, 2.7 micron with a pre-column filter. The HPLC was conductedat a flow rate of 2 mL/minute of mobile phase water (0.1%trifluoroacetic acid) and acetonitrile as described in Table 1-A below:

TABLE 1-A HPLC Method TIME % WATER % ACETONITRILE 0.00 70 30 0.25 70 304.00 5 95 4.25 70 30 5.00 70 30The retention times shown in Table 1-B below were observed:

TABLE 1-B HPLC Retention Times TIME COMPOUND 0.3 minutes2,5-dichlorobenzene diazonium sulfate 0.7 minutes 3-chloroaniline 1.9minutes 2,5-dichlorophenol 2.2 minutes 2,5-dichloroaniline 2.5 minutes1,4-dichloronitrobenze 2.9 minutes 1,4-dichlorobenzeneDisappearance of the 2,5-dichloroaniline peak on HPLC generallyindicated that the 2,5-dichloroaniline had been converted to the2,5-dichlorobenzene diazonium.

C. Gas Chromatography Mass Spectroscopy Method

Gas chromatography mass spectroscopy was performed on an Agilent systemusing a J&W 122-5535 DB-5MS-UI (0.25 mm×0.25 μm×30 m) column. Method: 1minute hold at 80° C.; 2 to 9 minute gradient 80° C. to 320° C.; 1minute hold at 320° C. Helium at 54 mL/minute flow, flame ionizationdetector (FID detector), and 1 μL injection.

D. Nuclear Magnetic Resonance Method

Nuclear magnetic resonance was run on a Brucker 600 MHz instrument.Deuterated solvents from Cambridge Isotope Laboratories, Ltd. includingmethanol, chloroform and dimethylsulfoxide were used as required.

E. Water Content Method

Percent water by weight determination was run on a Mettler DL18 KarlFischer instrument using Aqua Star CombiTitrant 5 acquired from EMDMillipore.

Example 2 Analytical Method (2,5-Dichlorobenzene Diazonium)

An analytical method was developed for evaluating the conversion of2,5-dichloroaniline to 2,5-dichlorobenzene diazonium in thediazotization reaction:

The 2,5-dichlorobenzene diazonium produced was not isolated, but insteadwas quenched with hypophosphorous acid (H₃PO₂) and converted to thecorresponding 1,4-dichlorobenzene:

Although the primary product of the conversion was 1,4-dichlorobenzene,it was observed that the hypophosphorous acid reaction produced otherminor by-products as detected by HPLC. The amount of 1,4-dichlorobenzeneproduced was then determined and that value was used to calculate theextent to which the initial amount of the 2,5-dichloroaniline charged tothe reaction was converted to the 2,5-dichlorobenzene diazonium.

Specifically, after the reaction medium comprising the2,5-dichloroaniline was treated with sodium nitrite and warmed to roomtemperature, an aliquot (approximately 200 mg) of the resulting reactionmixture was weighed into a 10 mL volumetric flask, and a volume ofhypophosphorous acid (50% weight/weight solution of hypophosphorousacid/water; approximately 10 times the volume of the reaction mixturealiquot) was added to the flask and the quenched mixture agitated forfive minutes at room temperature in a manner similar to the analyticalmethod reported in J. Org. Chem. Vol. 42, No. 8, 1977; J. Am. Chem. Soc.Vol. 72, No. 7, 1950. The quenched mixture then was diluted withmethanol (up to 10 mL) to dissolve any precipitate present and analyzedby HPLC. Response factors were developed for 1,4-dichlorobenzene andused to quantify that compound.

An aliquot of the reaction mixture also can be evaluated withouthypophosphorous treatment to measure the remaining 2,5-dichloroanilineusing appropriate response factors and then subtracting the measuredamount from the initial amount of the 2,5-dichloroaniline charged to thereaction to determine the corresponding amount of 2,5-dichlorobenzenediazonium produced.

Example 3 Diazotization/Hydroxylation in Sulfuric Acid (Biphasic Reflux)

2,5-Dichloroaniline (105 mmol, Sigma Aldrich) was recrystallized from125 mL of ethanol/water (3/2 volume/volume) to yield fine, off-whitecrystals of 2,5-dichloroaniline (89.6% yield). In a first experiment,16.1 g (123 mmol) of a 75% (weight percent) sulfuric acid solution inwater was added to 12.3 mmol of the recrystallized 2,5-dichloroanilinein an exothermic reaction that increased the temperature of theresulting mixture to about 60° C. The mixture was stirred vigorously ina 40 mL beaker while the temperature was reduced to about 10 to 20° C.using a cold water bath. Cooling produced a lumpy suspension of the2,5-dichloroaniline diazonium sulfate salt. A spatula was used tofurther grind and pulverize the suspension until it the suspension wassmooth. Sodium nitrite (910 mg, 13.2 mmol) was added to the suspensionin one portion resulting in the evolution of an orange gas (NO_(x)) andproducing a heterogeneous mixture. The mixture was stirred at roomtemperature for one hour. Solid sulfamic acid (80 mg, 0.9 mmol) wasadded and the mixture stirred for an additional 30 minutes. The viscousand corrosive mixture was then aliquotted into heated xylenes (13.5 mLat about 125° C.) via pipette over a 10 minute period. The mixture wasstirred at reflux for 30 minutes. Stirring was stopped and the mixturewas allowed to cool to room temperature overnight. While in the reactionvessel, the phases partitioned. The xylene layer was isolated and the2,5-dichlorophenol yield determined (6.26%) using HPLC response factors.2,5-Dichloroaniline diazonium and unreacted 2,5-dichloroaniline weredetected in the aqueous phase but not quantified.

The low yield suggested that the 2,5-dichloroaniline diazonium did notfully form or the hydrolysis reaction failed. It was hypothesized thatpoor solubility of the 2,5-dichloroaniline sulfate salt and the2,5-dichloroaniline diazonium intermediate likely contributed to the lowyield of the 2,5-dichlorophenol product. To fully dissolve the2,5-dichloroaniline and ensure the formation of the sulfate salt, fouradditional experiments were performed in which the2,5-dichloroaniline/sulfuric acid solution was heated to 94° C. toprovide a homogenous solution. The solution was cooled to about 10° C.to 20° C. and became a heterogeneous mixture. The sodium nitrite thenwas added piecewise over a 15 minute period. The hydrolysis wasperformed in xylenes as described above to give yields of the2,5-dichlorophenol product ranging from 23% to 50% as reported in Table3-A below:

TABLE 3-A 2,5-Dichlorophenol Yield (Sulfuric Acid/Biphasic Reflux) NaNO₂1.07 1.07 1.07 1.15 1.15 Equivalents Nitrite Quench Sulfamic NoneSulfamic None Sulfamic % Unreacted Yes  5.33%  8.38%  3.48%  0.93%2,5-DCA % Yield 2,5-DCP 6.26% 49.92% 23.30% 44.10% 28.68% Clean ProductNo No No No No Peak* *Refers to the HPLC of the organic phasepost-hydrolysis.

Example 4 Diazotization/Hydroxylation in Sulfuric Acid (Distillation)

2,5-Dichloroaniline (8.95 mmol) was added to a reactor containingconcentrated sulfuric acid (4 mL) and the mixture was heated to 65° C.to dissolve all of the 2,5-dichloroaniline. The resulting solution wascooled to 2° C. and formed a heterogeneous slurry. A solution of sodiumnitrite (9.51 mmol) in sulfuric acid (4 mL) was added to the slurry overa 15 minute period with a maximum temperature of 7° C. being reached.The slurry was slowly warmed to room temperature, a distillationapparatus and receiving flask attached, and the slurry was heated to157° C. Water (25 mL) was added to the reactor via an addition funnelover a 1.5 hour period. Heating and distillation continued for another2.5 hours in order to azeotrope the 2,5-dichlorophenol produced andwater into the receiving flask.

Upon cooling of the distillate, the 2,5-dichlorophenol productprecipitated as a white solid (44% isolated yield of solid product withan additional 4.5% in the distillate that could have been extracted withorganic solvent). No by-products formed and unreacted2,5-dichloroaniline (9%) was recovered in the aqueous phase of thereactor. Formation of the 2,5-dichlorobenzene diazonium again appearedto be hindered by solubility of the 2,5-dichloroaniline in sulfuricacid.

Example 5 Solubility Study

Three different commercially available sources of 2,5-dichloroaniline(Sigma, Acros, and AlfaAesar) were evaluated for solubility in severaldifferent solvents under the specific conditions reported in Table 5-A.The 2,5-dichloroaniline obtained from Sigma was evaluated with andwithout milling. Results from the study are reported in Table 5-A.

In general, the 2,5-dichloroaniline was readily soluble in acetic acidand trifluoroacetic acid at all temperatures. In contrast, it wasinsoluble in concentrated hydrochloric acid, 75% sulfuric acid(weight/weight sulfuric acid/water), and formic acid at all temperaturestested. Although 2,5-dichloroaniline was soluble in concentratedsulfuric acid at 80° C., solubility at the lower temperatures testedstill was limited. Milling the 2,5-dichloroaniline did appear to improvesolubility in concentrated sulfuric acid.

When sulfuric acid was added to the milled or unmilled2,5-dichloroaniline, the 2,5-dichloroaniline clumped up and formed a“crust” on itself. It is hypothesized that this crust is a2,5-dichloroaniline sulfate salt that forms and creates a salt capsuleenclosing the 2,5-dichloroaniline thereby further reducing2,5-dichloroaniline solubility. With vigorous stirring by stir bar orpaddle-equipped stir rod, the mixture containing the “crusted”2,5-dichloroaniline typically can be converted to a slurry of the2,5-dichloroaniline sulfate salt.

TABLE 5-A 2,5-Dichloroaniline Solubility (Different Solvents/Conditions)EXOTHERMIC SOLVENT TEMPERATURE SOURCE MILLED? SOLVENT MOLARITY ADDITION10° C. 25° C. 80° C. Sigma No Conc. H₂SO₄ 2.24 Yes Insoluble InsolubleSoluble Sigma No Conc. HCl 2.24 Slight Insoluble Insoluble InsolubleSigma No Glacial Acetic Acid 2.24 No Solvent Froze Soluble Soluble SigmaNo Formic Acid (88%) 2.24 No Insoluble Insoluble Insoluble Sigma No 75%H₂SO₄ 2.24 Slight Insoluble Insoluble Insoluble Sigma No TrifluoraceticAcid 2.24 No Soluble Soluble Soluble Acros No Conc. H₂SO₄ 2.24 YesPartial Partial Soluble Acros No Glacial Acetic Acid 2.24 No SolubleSoluble Soluble Acros No Conc. H₂SO₄ 1.12 Yes Partial Soluble SolubleAcros No Glacial Acetic Acid 1.12 No Soluble Soluble Soluble AlfaAesarNo Conc. H₂SO₄ 1.12 Yes Partial Partial Soluble AlfaAesar No GlacialAcetic Acid 2.24 No Soluble Soluble Soluble Sigma Yes Conc. H₂SO₄ 2.13Yes Soluble Soluble — Sigma Yes Conc. H₂SO₄ 1.16 Yes Soluble Soluble —Sigma Yes Conc. H₂SO₄ 0.58 Yes Soluble Soluble — Sigma Yes GlacialAcetic Acid 1.16 No Soluble Soluble — Sigma Yes Glacial Acetic Acid 2.24No Soluble Soluble —

Example 6 Diazotization in Acetic Acid

Acetic acid (4 mL) was added to a beaker containing 1.45 g (89.5 mmol)of 2,5-dichloroaniline. The reaction mixture was chilled in an ice bathto 12° C. and sodium nitrite (0.81 g, 11.74 mmol, 1.07 equivalents) in 4mL water was added via pipette over a period of 30 minutes. An orangegas evolved and the reaction mixture turned thick and orange-yellow.After the addition of the sodium nitrite, the reaction mixture wasstirred at 12° C. for 30 minutes. The reaction mixture was storedovernight at room temperature. The mixture was added via pipette over aperiod of 30 minutes to a reactor containing refluxing sulfuric acid(8.8 mL). Distillation occurred over a three hour period during which atotal of 50 mL water was added to the refluxing mixture. HPLC indicatedthe reactor contained mostly 2,5-dichloroaniline and the distillatecontained less than 1% 2,5-dichlorophenol generation.

Example 7 Diazotization in Acetic Acid/Sulfuric Acid

A. Diazotization Reaction

2,5-Dichloroaniline (8.95 mmol) was dissolved in acetic acid (16.9 mL,32.9 equivalents) and sulfuric acid (5.4 mL, 11.2 equivalents) was thenadded. The 2,5-dichloroaniline initially remained in solution afteraddition of the sulfuric acid, but the solution became a thick, opaque,homogenous mixture as it was cooled to 10° C. Sodium nitrite was addeddrop wise as an aqueous solution (12.3 mmol, 1.4 equivalents, in 5.6 mLwater). As sodium nitrite addition continued, 2,5-dichlorobenzenediazonium formed and was solvated. HPLC at this time indicated there wasno remaining 2,5-dichloroaniline. The resulting 2,5-dichlorobenzenediazonium solution then was added drop wise to a refluxing(approximately 100° C.) solution of sulfuric acid (8.8 mL) and water (36mL) in a reactor not equipped with a distillation arm, and stirred for30 minutes. HPLC, however, did not indicate the presence of any2,5-dichlorophenol in the refluxed solution. It is believed, however,that an increased reactor temperature and the addition of a distillationarm to the reactor would have resulted in the production of some amountof 2,5-dichlorophenol.

B. Diazotization Reaction (Sulfuric Acid Charge)

A study was conducted to evaluate the effect of the sulfuric acid chargeon the conversion of 2,5-dichloroaniline to the diazonium. In thisstudy, the acetic acid charge was maintained constant (18 equivalents)and the sulfuric acid charge was incrementally reduced.

Acetic acid (10.0 mL, 18 equivalents) was added to a series of beakerscontaining 2,5-dichloroaniline (1.50 g, 9.26 mmol). In separateexperiments, decreasing equivalents of sulfuric acid (8.26 to 1.0equivalents) were added to the beakers. The reaction mixtures werechilled in an ice bath (0° C. to 10° C.) and sodium nitrite_((aq)) (3.24mL, 3 M, 1.05 equivalents) was added via syringe pump at a rate of 0.4mL/minute with a subsurface flexible needle. After the addition wascomplete, the reaction mixtures were allowed to come to roomtemperature, and aliquots were removed for treatment withhypophosphorous acid to convert any diazonium produced to1,4-dichlorobenzene. The relative ratios of the HPLC peak areas detectedat 280 nm for the 2,5-dichloroaniline remaining and the1,4-dichlorobenzene produced are reported in Table 7-A below and shownas a bar chart in FIG. 1.

TABLE 7-A Diazonium Yield Versus Sulfuric Acid Charge 2,5- 1,4- SULFURICACID DICHLOROANILINE DICHLOROBENZENE EQUIVALENTS (HPLC PEAK RATIO) (HPLCPEAK RATIO) 8.26 28.9% 71.1% 6.61 8.8% 91.2% 5.78 3.3% 96.7% 4.96 1.8%98.2% 4.13 1.4% 98.6% 2.48 0.0% 100.0% 1.00 49.5% 50.5%

Reducing the sulfuric acid charge from 8.26 equivalents to 2.48equivalents actually increased conversion of 2,5-dichloroaniline to thediazonium. Below 2.48 equivalents of sulfuric acid, however, conversionto the diazonium decreased.

C. Diazotization Reaction (Acetic Acid Charge)

A similar study also was conducted to evaluate the effect of the aceticacid charge on the conversion of 2,5-dichloroaniline to the diazonium.In this study, the sulfuric acid charge was maintained constant (2.5equivalents) and the acetic acid charge was incrementally reduced.

Decreasing amounts of amounts of acetic acid (10 to 2.8 mL, 18 to 5equivalents) were added to a series of beakers containing2,5-dichloroaniline (1.50 g, 9.26 mmol). Sulfuric acid (2.27 mL, 2.5equivalents) was then added to each beaker. The reaction mixtures werechilled in an ice bath (0° C. to 10° C.) and sodium nitrite(aq) (3.24mL, 3 M, 1.05 equivalents) was added via syringe pump at a rate of 0.4mL/minute with a subsurface flexible needle. After the addition wascomplete, the reaction mixtures were allowed to come to roomtemperature, and aliquots were removed for treatment withhypophosphorous acid to convert any diazonium produced to1,4-dichlorobenzene. The relative ratios of the HPLC peak areas detectedat 280 nm for the 2,5-dichloroaniline remaining and the1,4-dichlorobenzene produced are reported in Table 7-B below and shownas a bar chart in FIG. 2.

TABLE 7-B Diazonium Yield Versus Acetic Acid Charge 2,5- ACETIC ACIDDICHLOROANILINE 1,4-DICHLOROBENZENE EQUIVALENTS (HPLC PEAK RATIO) (HPLCPEAK RATIO) 18.0 0.0% 100.0% 15.0 0.0% 100.0% 12.0 0.0% 100.0% 11.0 0.0%97.5% 10.0 0.0% 97.6% 9.0 0.0% 97.1% 8.0 0.0% 96.8% 7.0 0.0% 98.7% 6.06.7% 88.8% 5.0 5.3% 93.4%

Reducing the acetic acid charge from 18.0 equivalents to 7.0 equivalentsunder the conditions tested did not materially decrease solubility orconversion to the diazonium. At acetic acid charges below 7.0equivalents, however, decreases in solubility and conversion to thediazonium were observed.

D. Diazotization Reaction

A solution of acetic acid (7.78 mL, 7 equivalents) and sulfuric acid(4.54 mL, 2.5 equivalents) was added to a beaker containing2,5-dichloroaniline (3.00 g, 18.52 mmol). The resulting mixture waschilled in an ice bath (0° C. to 10° C.) and sodium nitrite_((aq)) (6.48mL, 3 M, 1.05 equivalents) was added via syringe pump at a rate of 0.4mL/minute with a subsurface flexible needle. After the addition wascomplete, the reaction mixture was allowed to come to room temperature,and an aliquot was removed for treatment with hypophosphorous acid toconvert any diazonium produced to 1,4-dichlorobenzene. HPLC indicatedcomplete conversion of the 2,5-dichloroaniline to 1,4-dichlorobenzene.

Example 8 Sodium Nitrite Equivalents

A study was conducted to evaluate the equivalents of sodium nitratenecessary for full conversion of 2,5-dichloroaniline to2,5-dichlorobenzene diazonium. Specifically, five diazonium formationreactions were run with differing equivalents of sodium nitrite (0.90 to1.10). In each case, 2,5-dichloroaniline (9.26 mmol) was dissolved inacetic acid (18 equivalents) and then sulfuric acid (8.26 equivalents)was added. The solution was chilled to 10° C. and sodium nitrite wasadded via syringe pump at a rate of 0.4 mL/min with a subsurfaceflexible needle. Each diazonium formation reaction was sampled at 30minutes, 60 minutes, and 90 minutes, and the aliquot treated with10×H₃PO₂ (50% by weight in water). The relative ratios of the HPLC peakareas detected at 280 nm for the 2,5-dichloroaniline remaining and the1,4-dichlorobenzene produced are reported in Table 8-A and shown as abar chart in FIG. 3. Each data point reported represents the averagevalue for the three intervals measured because the formation of the2,5-dichlorobenzene diazonium was very fast and there was no differencein the conversion over time. 2,5-Dichlorobenzene diazonium formationappeared to be complete between 1.00 and 1.05 equivalents of sodiumnitrite.

TABLE 8-A Diazonium Yield Versus Sodium Nitrite Charge EquivalentsSodium Nitrite Relative to 2,5-Dichloroanaline 0.90 0.95 1.00 1.05 1.10Average % Peak Area: 42.0% 28.4% 9.3% 0.0% 0.0% 2,5-DichloroanalineAverage % Peak Area: 58.0% 71.6% 90.7% 100.0% 100.0% 1,4-Dichlorobenzene

2,5-Dichlorobenzene diazonium also was prepared at room temperatureusing the same acetic acid/sulfuric acid reaction medium described aboveand 1.05 equivalents of sodium nitrite. The mixture was stored at roomtemperature for two weeks and no degradation in the diazonium wasobserved.

Example 9 Sodium Nitrate Addition Method

A study was conducted to evaluate the effect of the method for addingsodium nitrite to the reaction medium containing the 2,5-dichloroanilineon the conversion of the 2,5-dichloroaniline to 2,5-dichlorobenzenediazonium.

In various experiments, sodium nitrite was added: (i) piecewise as asolid, (ii) as a solution in sulfuric acid, (iii) as an aqueoussolution, or (iv) as pre-made nitrosylsulfuric acid. The primaryobjective was to evaluate whether such addition methods affected the insitu conversion of the nitrite to nitrous acid, the subsequent in situconversion of the nitrous acid to nitrosylsulfuric acid, and/or thereaction of the nitrosylsulfuric acid with the 2,5-dichloroaniline toform the intended diazonium.

A. Addition of Solid Sodium Nitrite

Piecewise solid addition presented a challenge for consistent,controlled addition. When too much sodium nitrite was added to thesulfuric acid (i.e., all of the sodium nitrite did not dissolveimmediately), the nitrous acid decomposed after formation. In general,when the solution temperature was too warm or the nitrite concentrationwas too high, the nitrous acid decomposed to water, nitrogen dioxide andnitric oxide. When decomposition occurred, gas evolution (an orange gas)and an increase in solution temperature were observed. When suchdecomposition occurred, a full equivalent of nitrous acid was notavailable to react with sulfuric acid to form nitrosylsulfuric acid insitu, and the reaction of such nitrosylsulfuric acid with the2,5-dichloroaniline to form the intended amount of diazonium did nottake place.

Sulfuric acid (20.23 g, 11.4 equivalents) was added to a beakercontaining 2,5-dichloroaniline (3.00 g, 18.52 mmol). The reactionmixture was cooled to room temperature in an ambient water bath, andsolid sodium nitrite (1.34 g, 19.44 mmol, 1.05 equivalents) was addedpiecewise over a period of 15 minutes. After the addition was complete,an aliquot was removed for treatment with hypophosphorous acid toconvert any diazonium produced to 1,4-dichlorobenzene. HPLC indicated94% conversion of the 2,5-dichloroaniline to 1,4-dichlorobenzene.

B. Addition of Sodium Nitrite in Concentrated Sulfuric Acid

An attempt was made to add a solution of sodium nitrite in concentratedsulfuric acid (greater than 4 M) to the solvent system containing the2,5-dichloroaniline using a syringe pump. The addition was notsuccessful because the pressure the pump applies to the syringe plungercaused the contents of the syringe to crystallize out of solution.

Sulfuric acid (30.07 g, 16.6 equivalents) was added to a beakercontaining 2,5-dichloroaniline (3.00 g, 18.52 mmol). The reactionmixture was cooled to room temperature, and a solution of sodium nitrite(1.34 g, 1.05 equivalents) and sulfuric acid (8 g) was added drop wisevia syringe with a subsurface needle. The syringe and needle becameplugged when the sodium nitrite crashed out of solution under thepressure of the syringe. An additional 11.5 g of sulfuric acid wasneeded to solvate the syringe contents, and the resulting solution wasadded drop wise over a period of 30 minutes. After the addition wascomplete, the reaction mixture was allowed to come to room temperature,and an aliquot was removed for treatment with hypophosphorous acid toconvert any diazonium produced to 1,4-dichlorobenzene. HPLC analysisindicated a 2,5-dichloroaniline to 1,4-dichlorobenzene peak absorbanceratio of 1:2.1.

C. Addition of Aqueous Solution of Sodium Nitrite

An aqueous solution of the sodium nitrite was added to a reaction mediumcontaining the 2,5-dichloroaniline. When the aqueous solution was addedto a reaction medium that was 2,5-dichloroaniline in concentratedsulfuric acid, the addition was very exothermic and analysis of theresulting solution showed a 2:1 ratio of diazonium to unreacted2,5-dichloroaniline. In contrast, when the aqueous solution was added toa reaction medium that was 2,5-dichloroaniline in acetic acid/sulfuricacid, however, the reaction was mildly exothermic.

Sodium nitrite_((aq)) (2.2 M, 1.05 equivalents) was added drop wise to2,5-dichloroaniline (18.52 mmol) in acetic acid/sulfuric acid andresulted in good conversion to the diazonium. Increasing the sodiumnitrite concentration to 3 M also provided good conversion to thediazonium. When the sodium nitrite concentration was increased from 3 Mto 6 M, however, conversion to the diazonium decreased to less than 70%.It is hypothesized that water plays a role in solvating the diazoniumand sodium bisulfate (a byproduct of the formation of nitrous acid), andthat sodium bisulfate precipitates out of solution as the amount ofwater present decreases.

Theoretically, the nitrous acid is less prone to decomposition andformation of the diazonium should be favored when the aniline sulfatesolution is chilled to a temperature between 0° C. to 10° C. There didnot appear to be a significant difference, however, in the formation ofthe diazonium at room temperature (about 25° C.) versus temperaturesranging from 0° C. to 10° C. The lower temperatures may not be requiredas long as stirring and subsurface addition of the sodium nitrite areadequate.

D. Addition of Nitrosylsulfuric Acid

Nitrosylsulfuric acid (40% by weight in concentrated sulfuric acid,Sigma-Aldrich) was added drop wise to a mixture of 2,5-dichloroanilinein sulfuric acid_((aq)) (60% by weight). The formation of the diazoniumwas quantitative, efficient, less exothermic, and less prone todecomposition. The reaction was repeated in 50% to 98% concentratedsulfuric acid with 2,5-dichloroaniline solubility increasing as sulfuricacid concentration increased. Similar results were obtained at allsulfuric acid concentrations, i.e., complete conversion to thediazonium.

To a beaker containing 2,5-dichloroaniline (3.00 g, 18.52 mmol) wasadded 60% by weight sulfuric acid_((aq)) (18.01 g, 110.17 mmol). Thesolution was warmed to 120° C. for 80 minutes to dissolve the2,5-dichloroaniline. At room temperature, nitrosylsulfuric acid (40% byweight in sulfuric acid) (6.25 g, 1.06 equivalents) was added viapipette subsurface to the mixture. After the addition was complete, thereaction was allowed to come to room temperature, and an aliquot wasremoved for treatment with hypophosphorous acid to convert any diazoniumproduced to 1,4-dichlorobenzene. HPLC indicated 96% conversion of the2,5-dichloroaniline to 1,4-dichlorobenzene.

As indicated by the experiments discussed above, the temperature andoverall sodium nitrite concentration affect the mechanics of the sodiumnitrite addition. One satisfactory approach (see Example 10) thatresulted in complete conversion to the diazonium involved the additionof an aqueous solution of sodium nitrite (3 M) at a temperature of 10°C. via a subsurface flexible needle (16 gauge) as delivered by a syringepump at 0.5 mL/min to the 2,5-dichloroaniline (18.52 mmol reactionscale) with overhead stirring in a mixed solvent system of acetic andsulfuric acid (7:2.5 molar ratio).

E. Drop Wise Addition to Concentrated Sulfuric Acid Reaction Medium

2,5-Dichloroaniline (18.52 mmol) was dissolved in concentrated sulfuricacid (8.27 mL, 8.38 equivalents) in a round-bottom flask equipped withan overhead stirrer. A solution of sodium nitrite (19.63 mmol, 1.06equivalents) in sulfuric acid (8.27 mL, 8.38 equivalents) was added dropwise to a stirring mixture of 2,5-dichloroaniline sulfate salt at 10° C.HPLC analysis indicated that approximately 20% of the2,5-dichloroaniline was unreacted. It is believed that due to solubilityand handling conditions quantitative formation of the diazonium usingonly 1.05 equivalents of sodium nitrite is not likely in a concentratedsulfuric acid solvent system under these conditions. In addition, it isfurther believed that sodium nitrite in sulfuric acid (unlike sodiumnitrite in an aqueous solution) is more likely to crash out of solutionunder increased pressure conditions (such as a syringe pump) at thisconcentration (0.164 g/mL). Using an addition funnel however, impedesdelivery of the sodium nitrite which is better delivered subsurface andat a low steady rate (as it would have been using a syringe pump.

Example 10 Diazotization in Acetic Acid/Sulfuric Acid

A. Experiment A

Concentrated sulfuric acid (13.62 g, 0.14 mol, 2.50 equivalents) wasadded to a solution of 2,5-dichloroaniline (9.00 g, 0.055 mol) in aceticacid (23.35 g, 0.39 mol, 7.00 equivalents) in a 250 mL round-bottomflask. The addition of the sulfuric acid was exothermic. The reactionmixture was allowed to cool to room temperature. It remained solubilizedand was stirred with an overhead paddle stirrer. The reaction mixturecontaining the 2,5-dichloroaniline was chilled (and became a slurry oncecooled to 0° C. to 10° C.) and a solution of sodium nitrite (19.44 mL, 3M, 1.05 equivalents) was added via syringe pump at 0.5 mL/minute. Theflexible needle tip was placed subsurface of the solution and an icewater bath was used to maintain the solution at a temperature between 0°C. to 10° C.

Approximately 20 μL of the solution was removed and reacted with 100 μLof hypophosphorous acid (40% by weight in water) in a 2 dram vial. Thealiquot was shaken for 30 seconds, diluted with 2 mL of methanol, andanalyzed by HPLC to determine the ratio of unreacted 2,5-dichloroanilineto 1,4-dichlorobenzene (i.e., the product of the deamination reaction ofdiazonium with hypophosphorous acid). HPLC indicated approximately 100%conversion of the 2,5-dichloroaniline to the 1,4-dichlorobenzene.

B. Experiment B

Concentrated sulfuric acid (4.54 mL, 2.50 equivalents) was added to asolution of 2,5-dichloroaniline (3.00 g, 18.52 mmol) in acetic acid(7.78 mL, 7.00 equivalents) in a beaker. The reaction mixture waschilled in an ice bath (0° C. to 10° C.) and sodium nitrite (6.48 mL, 3M, 1.05 equivalents) was added via syringe pump at a rate of 0.4mL/minute with a subsurface flexible needle. After the addition wascomplete, the reaction mixture was allowed to come to room temperature,and an aliquot was removed for treatment with hypophosphorous acid toconvert any diazonium produced to 1,4-dichlorobenzene. HPLC indicatedapproximately 100% conversion of the 2,5-dichloroaniline to1,4-dichlorobenzene.

Example 11 Diazotization/Hydroxylation in Acetic Acid/Sulfuric Acid(Biphasic Reflux)

In three separate experiments similar to the experiments previouslydiscussed in Example 3, sulfuric acid (15.00 g, 8.54 equivalents) wasadded to 2,5-dichloroaniline (8.95 mmol) in a solution of acetic acid(10.00 g, 18.61 equivalents). The mixture was stirred vigorously in a100 mL beaker while the temperature was reduced to about 10° C. using acold water bath. Sodium nitrite_((aq)) (1.21 or 1.37 equivalents asstated in Table 11-A) was added drop wise over 15 minutes to give aheterogeneous mixture. After the nitrite addition, sulfamic acid (0equivalents to 0.11 equivalents) was added to the mixture and themixture stirred for 10 minutes.

The mixture came to room temperature and was added via syringe pump to areactor set at 130° C. and containing xylenes (40 mL) over a 15 minuteto 90 minute period. The biphasic reaction mixture did not maintain theset temperature after the addition. The temperature stabilized at 97° C.to 111° C. even though the set temperature was at 130° C. The mixturewas stirred for 30 minutes to 120 minutes. Stirring was stopped and themixture was allowed to cool to room temperature, and the phasespartitioned. The xylene layer was isolated and the 2,5-dichlorophenolyield determined using HPLC response factors. The 2,5-dichlorophenolproduct yields ranged from 1% to 34% as reported in Table 11-A below:

TABLE 11-A 2,5-Dichlorophenol Yield (Biphasic Reflux) Acetic/SulfuricAcetic/Sulfuric Acetic/Sulfuric Diazonium Solvent (4:3) (4:3) (4:3)NaNO₂ Equivalents 1.37 1.21 1.21 NaNO₂ Addition Aqueous Aqueous AqueousNitrite Quench None None Sulfamic Reactor Temperature 97° C. 111° C. 111to 125° C. % Unreacted DCA    0%   0%   0% % Yield 2,5-DCP 33.41% 1.78%8.40% Clean Product Peak* No No No *Refers to the HPLC of the organicphase post-hydrolysis.

The reported data indicate that the diazonium formation was complete,but that the conversion to the 2,5-dichlorophenol was very low under thebiphasic conditions. As the 2,5-dichlorophenol formed, it was extractedinto the xylenes. A phase partition of the reactor contents should haveprovided a 2,5-dichlorophenol product that could be distilled to produceclean 2,5-dichlorophenol. Analysis of the impurities in the organicphase with GCMS found nitrated xylenes and other byproducts present.

Example 12 Diazotization/Hydroxylation in Acetic Acid/Sulfuric Acid(Steam Distillation)

A. Hydrolysis With Water

Prior to employing the steam hydrolysis approach discussed below, anexperiment was conducted to hydrolyze the diazonium in a reactor withwater as described below.

Concentrated sulfuric acid (9.86 g, 11.23 equivalents) was added to asolution of 2,5-dichloroaniline (1.45 g, 8.95 mmol) in acetic acid(17.70 g, 32.94 equivalents) in a beaker. The reaction mixture waschilled in an ice bath (0° C. to 10° C.) and sodium nitrite (0.85 g,1.37 equivalents) in water (6.50 mL) was added drop wise as to not raisethe reaction temperature over 10° C. After the addition was complete,the reaction mixture was allowed to come to room temperature, and HPLCindicated no 2,5-dichloroaniline present. All of the aniline is presumedto have been converted to the diazonium.

To a three-neck round bottom flask equipped with a receiving flask wasadded water (20 mL) and sulfuric acid (10 mL). The solution was heatedto 120° C., and the diazonium mixture (8.95 mmol) was added in portionsover one hour. Water (2×20 mL) was added at one hour and two hours, anddistillation continued for a total of four hours. The contents of thereceiving flask were extracted with ethyl acetate to provide a 10% yieldof 2,5-dichlorophenol while a 16% yield of 2,5-dichlorophenol wasquantified in the reactor.

B. Hydrolysis with Water (Drop Wise Addition to Reactor)

An experiment was conducted to hydrolyze the diazonium with water addeddrop wise to the reactor via an addition funnel as described below.

Concentrated sulfuric acid (7.36 g, 8.38 equivalents) was added to2,5-dichloroaniline (1.45 g, 8.95 mmol) in a beaker. The reactionmixture was chilled in an ice bath (0° C. to 10° C.) and sodium nitrite(0.81 g, 1.31 equivalents) in sulfuric acid (5 mL) was added drop wiseas to not raise the reaction temperature over 10° C. After the additionwas complete, the reaction mixture was allowed to come to roomtemperature.

To a three-neck round bottom flask equipped with a receiving flaskcontaining 2,5-dichlorobenzenediazonium sulfate (8.95 mmol) was addedwater (25 mL) via an addition funnel over a two hour period while thereactor was heated to 120° C. The contents of the receiving flask werefiltered by vacuum filtration to isolate solid 2,5-dichlorophenol (44%yield). The distillate filtrate was analyzed with response factors togive an additional 4.5% yield for 2,5-dichlorophenol.

C. Hydrolysis with Water (Present in Reactor)

Concentrated sulfuric acid (27.3 g, 24.1 equivalents) was added to asolution of 2,5-dichloroaniline (1.90 g, 11.74 mmol) in water (7.5 mL)in a beaker. The reaction mixture was chilled in an ice bath (0° C. to10° C.) and sodium nitrite (0.97 g, 1.20 equivalents) in water (5 mL)was added drop wise over 10 minutes. After the addition was complete,the reaction mixture was allowed to come to room temperature.

To a large vial containing 2,5-dichlorobenzenediazonium sulfate (11.7mmol) was added water (20 mL), and the vial was heated to 100° C. for2.5 hours. The reaction mixture was extracted with ethyl acetate andwater, but no 2,5-dichlorophenol was detected.

D. Hydrolysis with Water (Steam Distillation—Effect of Temperature)

A study was conducted to evaluate the use of steam distillation atvarying temperatures to hydrolyze the diazonium to the2,5-dichlorophenol product.

Concentrated sulfuric acid (60.00 g, 8.26 equivalents) was added to asolution of 2,5-dichloroaniline (12.00 g, 0.074 mol) in acetic acid(80.00 g, 17.99 equivalents) in a beaker. The reaction mixture waschilled in an ice bath (0° C. to 10° C.) and sodium nitrite (5.37 g,1.05 equivalents) in water (32 mL) was added subsurface via syringe pumpas to not raise the reaction temperature over 20° C. After the additionwas complete, the reaction mixture was allowed to come to roomtemperature, and HPLC indicated no 2,5-dichloroaniline present. All ofthe aniline is presumed to have been converted to the diazonium.

Sulfuric acid (40 mL) was added to a three-neck round bottom flaskequipped with a side-arm condenser, receiving flask, and subsurfacesteam inlet, and heated to a set temperature for the trial (104° C.,130° C., or 150° C.). Steam was charged at a set rate of approximately0.34 scf/minute. The diazonium mixture (19.6 mmol) was added via syringepump at 0.8 to 1.25 mL/minute. At the end of the addition, the steamcontinued for 10 minutes then was turned off. The reactor was cooled toroom temperature, and the yield of 2,5-dichlorophenol in the distillateand reactor were determined by response factors and summed. Results arereported in Table 12-A below. In general, 2,5-dichlorophenol yields werelower for reactions conducted at a temperature below 150° C.

TABLE 12-A 2,5-Dichlorophenol Yield Versus Reactor Temperature ReactorSet Temperature 104° C. 130° C. 150° C. Observed Exotherm 160° C. 185°C. 195° C. Unreacted Diazonium 77.7% 23.7% 0.0% % Yield2,5-Dichlorophenol 6.9% 48.7% 95.9%

In addition, the amount of water in the distillate and the reactor wasdetermined by Karl Fischer analysis. Any water added as part of a rinseor the diazonium solution was quantified and subtracted out to determinethe amount of water added as steam. The amount of water collected andlength of steam input into the reactor determine an approximate steamflow rate.

E. Hydrolysis with Water (Steam Distillation—Steam Rate)

A study was conducted to evaluate the use of steam distillation atvarying steam rates to hydrolyze the diazonium to the 2,5-dichlorophenolproduct. Reducing the mass of water collected in the distillate can bebeneficial for multiple reasons including situations where the2,5-dichlorophenol product will be extracted with xylenes. The requiredamount of xylenes needed to extract 2,5-dichlorophenol was determined tobe 85% by weight of xylene and 2,5-dichlorophenol solution (i.e., about17 mL of xylenes for every 18.5 mmol of 2,5-dichlorophenol). Initialhydrolysis reactions employed about 0.3 scf/min to about 0.4 scf/min ofsteam and generated in excess of 300 g of water in the distillate.Additional hydrolysis reactions were conducted using reduced steam ratesthereby lowering the mass of the distillate collected.

Sulfuric acid (40 mL) was added to a three-neck round bottom flaskequipped with a side-arm condenser, receiving flask, and subsurfacesteam inlet, and heated to 150° C. Steam was charged at a set rate foreach trial (0.38 scf/minute to 0.06 scf/minute). The diazonium mixture(18.52 mmol) was added via syringe pump at 1.25 mL/minute. At the end ofthe addition, the steam continued for five minutes then was turned off.The heat continued until the distillation head temperature dropped below90° C. (approximately five minutes), then the reactor was cooled to roomtemperature. The yield of 2,5-dichlorophenol in the distillate andreactor were determined by response factors and summed. Results arereported in Table 12-B below.

TABLE 12-B 2,5-Dichlorophenol Yield Versus Steam Rate LENGTH TOTAL MASSOF ACID EQUIV. RATIO YIELD STEAM OF WATER STEAM (ACETIC ACID:SULFURICSUM RATE COLLECTED CHARGE REACTION ACID) (%) (scf/min) (g) (Minutes) 118.0:8.3  91% 0.35 — 40 2 18.0:2.5  84% 0.38 312 39 3 7.0:2.5 95% 0.18117 31 4 7.0:2.5 96% 0.10 57 24 5 7.0:2.5 89% 0.06 31 23 6 7.0:2.5 84%0.09 42 22 7 7.0:2.5 81% 0.10 42 23

Example 13 Hydrolysis in Acetic Acid/Sulfuric Acid (Steam Distillation)

A diazonium salt solution (prepared using an acetic acid/sulfuric acidmedium) was loaded into a tared gas-tight syringe equipped with a 14gauge flexible needle tip and weighed. Approximately 40 g ofconcentrated sulfuric acid (greater than 98% by weight) was added to a250 mL 3-neck reactor equipped with a stir bar, side-arm condenser withreceiving flask, sub-surface steam inlet, heating mantle, and JKEMtemperature probe. When the acid temperature reached 150° C., steam wasapplied at approximately 0.1 scf/minute to 0.2 scf/minute. At the sametime, addition of the diazonium solution began at 1.25 mL/minute withthe tip of the flexible needle at near or sub-surface of the sulfuricacid. An initial exotherm gave a reactor temperature of 180° C. to 220°C. The distillation head maximum temperature reached 110° C.

At the end of the diazonium addition (approximately 10 minutes), thesyringe was weighed to determine amount of diazonium added (18.51 mmol).The steam charge continued for 5 minutes post addition. The reactor washeated until the distillation head temperature lowered to 90° C. and noadditional distillate was being collected (approximately 10 minutes).Some of the 2,5-dichlorophenol was a solid at the bottom of thereceiving flask and some was dissolved in the distillate. The receivingflask contents were extracted with 17 mL xylenes (based on 15% by weight2,5-dichlorophenol in the xylenes post-extraction) and the phasespartitioned. 2,5-Dichlorophenol residue was present in the apparatus sothe apparatus was rinsed with methanol and the washings were collected.HPLC quantitative analysis by response factors gave percent yield of2,5-dichlorophenol in the distillate xylene phase (65.7%), distillateaqueous phase (5.1%), reactor residue (6.2%), and apparatus rinse(17.7%) were performed. Results of percent yield were summed to give anoverall yield (94.8%). An aliquot from the reactor was treated withhypophosphorous acid to determine residual diazonium content (0%).

Proton NMR Data

2,5-dichlorophenol: ¹H NMR (600 MHz, CDCl₃) δ 7.26 (d, 1H, J=10.2 Hz),7.06 (d, 1H, J=2.4 Hz), 6.92 (dd, 1H, J=6.0, 2.4 Hz), 5.62 (br s, —OH).

2,5-dichloroaniline: ¹H NMR (600 MHz, CD₃OD) δ 7.14 (d, 1H, J=8.4 Hz),6.82 (d, 1H, J=2.4 Hz), 6.58 (dd, 1H, J=6.0, 2.4 Hz).

2,5-dichlorobenzenediazonium: ¹H NMR (600 MHz, D₂O) δ 8.52 (d, 1H, J=2.4Hz), 8.04 (dd, 1H, J=6.6, 2.4 Hz), 7.80 (d, 1H, J=9.0 Hz).

Example 14 Quench Prior to Hydrolysis Step

A study was conducted to evaluate the effect of quenching excess nitrousacid with sulfamic acid or urea necessary to prevent the formation ofby-products in the hydrolysis step. Sulfamic acid and urea react withand decompose nitrous acid as shown below:

In this study, 2,5-dichlorophenol was stirred at 120° C. in the presenceor absence of sodium nitrite and/or sulfamic acid. The2,5-dichlorophenol itself was stable and either dissolved or melted inthe various solvents at 120° C. Upon addition of sodium nitrite to thesolution and heating at 120° C. for 30 minutes, all of the solutions hadsome byproduct formation. The experiments were repeated with sulfamicacid added at 1.1 times the sodium nitrite equivalents with heating to120° C. for 30 minutes as before. Byproduct formation was reduced, andonly the solutions containing sulfuric acid had byproducts. Results arereported in Table 14-A below.

TABLE 14-A 2,5-Dichlorophenol Stability at Specific Temperatures, Times,and Reagent/Solvent Conditions) SULFURIC ACETIC ACID, ACID, WATER,SULFURIC CONDITIONS WATER WATER, XYLENES XYLENES ACID, WATER 60 minutesat No No No Byproducts No Byproducts 120° C. Byproducts Byproducts 30minutes at Possible Nominal Nitrated DCP, Nitrated DCP, 120° C.Biphenyls Byproducts Unidentified Unidentified 0.2 Eq. NaNO₂ Byproducts,Byproducts, Possible Possible Biphenyls Biphenyls 30 min 120° C. NoNominal Unidentified Unidentified 0.2 Eq. NaNO₂ Byproducts ByproductsByproducts Byproducts 0.22 Eq. H₃SO₃N

Use of urea or sulfamic acid as described in this example did not appearto affect the yield of the 2,5-dichlorophenol in a hydrolysis reaction.A brown/orange reactor residue typically was observed in the hydrolysisreactions described in the prior examples. Use of urea or sulfamic acid,however, did not appear to reduce this reactor residue. In general, itappears that sulfamic acid or urea can be charged at 0.05% to 0.10% ofthe 2,5-dichloroaniline charge to offset the excess sodium nitritecharge, either as a solid or as an aqueous solution after the diazoniumcools to room temperature.

Example 15: Parallel Addition of 2,5-Dichloroaniline and Nitroso Source

A. Parallel Addition of 2,5-Dichloroaniline and Nitrosylsulfuric Acidinto Sulfuric Acid Solution

Concentrated sulfuric acid (6.05 g, 0.06 mol, 0.5 eq.) was placed in a250 mL three-neck round-bottom flask equipped with an overhead stirrerand cooled in an ice-water bath. A solution of 2,5-dichloroaniline inacetic acid (25 wt/wt %, 76.76 g, 0.12 mol) and a solution ofnitrosylsulfuric acid in sulfuric acid (40 wt/wt %, 41.11 g, 1.08 eq.)were added in parallel via two individual syringe pumps. The addition ofthe aniline solution was carried out by dripping the solution into thestirring reaction while the addition of the nitrosylsulfuric acidsolution was carried out by introducing the solution at the subsurfaceof the reaction medium. The addition rate was controlled such that bothadditions were completed in 41 minutes, during which time the reactioninternal temperature was maintained below 15° C. After the addition, theformed diazonium salt solution was allowed to come to room temperature.

B. Parallel Addition of 2,5-Dichloroaniline and Nitrosylsulfuric Acidinto a Mixed Solution of Acetic Acid and Sulfuric Acid

Acetic acid (99%, 200.15 g, 3.33 mol, 5.4 eq.) was placed in a 1500 mLglass vessel equipped with an overhead stirrer. The solution was cooledin an ice-water bath and concentrated sulfuric acid (96%, 160.05 g, 1.57mol, 2.54 eq.) was added. A solution of 2,5-dichloroaniline in aceticacid (26.0 wt/wt %, 384.6 g, 0.62 mol) and a solution ofnitrosylsulfuric acid in sulfuric acid (40 wt/wt %, 202.5 g, 1.03 eq.)were added in parallel. The addition of the nitrosylsulfuric acidsolution was carried out by introducing the solution at the subsurfaceof the reaction medium. The addition rate was controlled such that bothadditions were completed in 2.15 hours, during which time the reactioninternal temperature was maintained between—4° C. to 10° C. After theaddition, the formed diazonium salt solution was allowed to come to roomtemperature and was stirred at least for an additional 2 hours.

Experiment B was repeated except that a solution of 2,5-dichloroanilinein acetic acid (29.1 wt/wt %, 345.0 g, 0.62 mol) was used and theparallel additions were completed in 2.5 hours.

C. Parallel Addition of 2,5-Dichloroaniline and Sodium Nitrite intoSulfuric Acid Solution

Concentrated sulfuric acid (15.84 g, 2.6 eq.) was placed in a 250 mLthree-neck round-bottom flask equipped with an overhead stirrer andcooled in an ice-water bath. A solution of 2,5-dichloroaniline in aceticacid (19.23 wt/wt %, 50.91 g, 0.060 mol) was loaded into an additionfunnel and a solution of sodium nitrite in water (20 wt/wt %, 22.30 g,1.07 eq.) was loaded into a syringe pump. The addition of the sodiumnitrite solution was carried out by introducing the solution at thesubsurface of the reaction medium. The addition rate was controlled suchthat both additions were completed in 60 minutes, during which time thereaction internal temperature was maintained below 15° C. After theaddition, the formed diazonium salt solution was allowed to come to roomtemperature.

D. Parallel Addition of 2,5-Dichloroaniline and Sodium Nitrite into aMixed Solution of Acetic Acid and Sulfuric Acid

Sulfuric acid (96%, 16.43 g, 2.50 eq.) and acetic acid (99%, 22.27 g,5.70 eq.) were added to a 250 mL three-neck round-bottom flask equippedwith an overhead stirrer. The flask was cooled in an ice-water bath. Asolution of 2,5-dichloroaniline in acetic acid (24.8 wt/wt %, 42.07 g,0.064 mol) was loaded into a tared gas-tight syringe and a solution ofsodium nitrite in water (20 wt/wt %, 23.25 g, 1.04 eq.) was loaded intoa separate syringe pump. The addition of the sodium nitrite solution wascarried out by introducing the solution at the subsurface of thereaction medium. The addition rate was controlled such that bothadditions were completed in 90 minutes, during which time the reactioninternal temperature was maintained below 15° C. After the addition wascomplete, the formed diazonium salt solution was allowed to come to roomtemperature.

E. Parallel Addition of 2,5-Dichloroaniline and Calcium Nitrite into aMixed Solution of Acetic Acid and Sulfuric Acid

In this experiment, calcium nitrite was used as the nitroso source inplace of sodium nitrite. As with sodium nitrite, this alternate alkalimetal likewise reacts with sulfuric acid to form nitrosylsulfuric acidin situ for diazotization of 2,5-dichloroaniline. Sulfuric acid (96%,16.44 g, 2.5 eq.) and acetic acid (99%, 22.67 g, 5.78 eq.) were added toa 250 mL three-neck round-bottom flask equipped with an overheadstirrer. The flask was cooled in an ice-water bath. A solution of2,5-dichloroaniline in acetic acid (25 wt/wt %, 42.73 g, 0.065 mol) wasloaded into a tared gas-tight syringe, and a solution of calcium nitritein water (10 wt/wt %, 45.28 g, 0.52 eq.) was loaded into a separatesyringe pump. The addition of the calcium nitrite solution was carriedout by introducing the solution at the subsurface of the reactionmedium. The addition rate was controlled such that both additions werecompleted in 90 minutes, during which time the reaction internaltemperature was maintained below 15° C. After the addition, the formeddiazonium salt solution was allowed to come to room temperature. Theinsoluble solids were filtered and the filtrate was subjected for nexthydroxylation step with water.

Diazonium salt solution filtrate (0.055 mol, 0.643 mmol/g) was loadedinto a first tared gas-tight syringe equipped with a 14-gauge flexibleneedle tip. Water (50.86 g, 2.82 mol) was loaded into a second taredgas-tight syringe equipped with a 16-gauge flexible needle tip. Sulfuricacid (96%, 20 g) was placed in a 500 mL three-neck round-bottom flaskequipped with a stir bar, a side-arm condenser with receiving flask, aheating mantle, and a JKEM thermocouple. When the acid temperaturereached 150° C., the diazonium salt solution and water were added inparallel via aforementioned two syringe pumps. The addition rates werecontrolled such that the diazonium salt solution addition was completedin 72 minutes and the water addition was completed in 82 minutes. After90 minutes, the heat was removed from the reactor and no additionaldistillate was collected afterwards. The contents in the receiving flaskwere weighed and isolated for analysis. HPLC quantitative analysis byresponse factors found the yield of 2,5-dichlorophenol in the distillatewas 63.4%.

Example 16: Hydrolysis in Acetic Acid/Sulfuric Acid (Water)

A. Hydrolysis with Water (Parallel Addition of Water and DiazoniumSolution

Diazonium salt solution was prepared as in Example 15-A by paralleladdition of 2,5-dichloroaniline and nitrosylsulfuric acid into asulfuric acid solution. The diazonium salt solution (0.054 mol, 0.953mmol/g) was loaded into a first tared gas-tight syringe equipped with a14-gauge flexible needle tip. Water (46.0 g, 2.55 mol, 47.2 eq.) wasloaded into a second tared gas-tight syringe equipped with a 16-gaugeflexible needle tip. Sulfuric acid (85%, 20 g, 3.19 eq.) was placed in a500 mL 3-neck round-bottom flask equipped with a stir bar, a side-armcondenser with receiving flask, a heating mantle, and a JKEMthermocouple. When the acid temperature reached 150° C., the diazoniumsalt solution and water were added in parallel via aforementioned twosyringe pumps. The addition rates were controlled such that thediazonium salt solution addition was completed in 33 minutes and thewater addition was completed in 70 minutes. The distillation headmaximum temperature reached 110° C.

The reactor was heated when the distillation head temperature droppedbelow 90° C. and no additional distillate was collected at the end ofapproximately 85 minutes. The contents in the receiving flask wereweighed and isolated for analysis. HPLC quantitative analysis byresponse factors found that the yield of 2,5-dichlorophenol in thedistillate was 79.5%.

B. Hydrolysis with Water (Water Addition Before and after ParallelAddition of Water and Diazonium Solution)

Diazonium salt solution was prepared as in Example 15-B by paralleladdition of 2,5-dichloroaniline and nitrosylsulfuric acid into a mixedsolution of acetic acid and sulfuric acid. The resulting diazonium saltsolution was evaluated for hydrolysis with water addition before andafter the parallel addition of water and diazonium solution. The resultsshow that the addition of water before and after the parallel additionimproved the isolated 2,5-dichlorophenol yield.

Parallel Addition Only:

The diazonium salt solution was subjected to hydrolysis only by paralleladdition of water and diazonium solution. Sulfuric acid (85% w/w, 502.7g, 14.18 eq) was placed in a reaction vessel and heated to 150° C.Diazonium salt solution (0.62 mol, 0.683 mmol/g) and water (950 g, 52.75mol) were added in parallel, during which the reaction internaltemperature was maintained from 135° C. to 170° C. The addition rateswere controlled such that both additions were completed in 5 hours 15minutes. After 6 hours 35 minutes, the heat was removed from the reactorand no additional distillate was collected afterwards. The contents inthe receiving flask were extracted into xylenes (3×300 g). HPLCquantitative analysis by response factors found that the yield of2,5-dichlorophenol in the xylene extracts was 71.1%.

Water Addition Before and after Parallel Addition:

The diazonium salt solution was subjected to hydrolysis with wateraddition before and after the parallel addition of water and diazoniumsolution. Diazonium salt solution (0.49 mol, 0.652 mmol/g) was loadedinto a first tared dropping funnel (500 mL). Water (880 g, 48.86 mol,98.96 eq.) was loaded into a second tared dropping funnel (1000 mL).Sulfuric acid (85%, 432 g, 7.58 eq.) was added to a 1500 mL five-neckglass vessel equipped with a mechanical stirring, a side-arm condenserwith receiving flask, and a heated oil bath. When the acid temperaturereached 165° C., water (about 40 mL) was slowly added until a constantdistillation of water in the distillation bridge was observed. At thistime, the diazonium salt solution and water were added in parallel,during which the internal temperature maintained above 150° C. Theaddition rates were controlled such that the diazonium salt solutionaddition was completed in 7 hours as controlled by maintaining theinternal temperature above 150° C. Additional water (approximately 40mL) was added after the diazonium addition was completed and the heatsource was then removed. The contents in the receiving flask wereweighed and isolated for analysis. HPLC quantitative analysis byresponse factors found that the yield of 2,5-dichlorophenol in thedistillate was 93.7%.

C. Hydrolysis with Parallel Addition (Water Vs. Steam)

Diazonium salt solution was prepared as in Example 15-C by paralleladdition of 2,5-dichloroaniline and sodium nitrite into sulfuric acidsolution. The resulting diazonium salt solution was evaluated forhydrolysis by parallel addition of a hydrolysis source and the diazoniumsolution. The hydrolysis source was either water or steam.

Parallel Addition of Water:

The diazonium salt solution was subjected to hydrolysis by the paralleladdition of water and diazonium solution. Diazonium salt solution (0.050mol, 0.686 mmol/g) was loaded into a first tared gas-tight syringeequipped with a 14-gauge flexible needle tip. Water (55.79 g, 3.10 mol,62.0 eq.) was loaded into a second tared gas-tight syringe equipped witha 16-gauge flexible needle tip. Sulfuric acid (77%, 20 g) was placed toa 250 mL three-neck round-bottom flask equipped with a stir bar, aside-arm condenser with receiving flask, a heating mantle, and a JKEMthermocouple. When the acid temperature reached 150° C., the diazoniumsalt solution and water were added in parallel via the two syringepumps. The addition rates were controlled such that both additions werecompleted in 82 minutes. After 90 minutes, the heat was removed from thereactor and no additional distillate was collected afterwards. Thecontents in the receiving flask were weighed and isolated for analysis.HPLC quantitative analysis by response factors found that the yield of2,5-dichlorophenol in the distillate was 55.6%.

Parallel Addition of Steam:

The diazonium salt solution was subjected to hydrolysis by the paralleladdition of steam and diazonium solution. Diazonium salt solution (0.051mol, 0.713 mmol/g) was loaded into a tared gas-tight syringe equippedwith a 14-gauge flexible needle tip. Sulfuric acid (77%, 20 g) wasplaced in a 250 mL three-neck round-bottom flask equipped with a stirbar, a side-arm condenser with receiving flask, a heating mantle, and aJKEM thermocouple. When the acid temperature reached 150° C., thediazonium salt solution addition was started via the syringe pump andthe steam charge (0.039 scf/min) was initiated. The addition rates werecontrolled such that the diazonium salt solution addition and the steamcharge were completed in 90 minutes. After 90 minutes, the heat wasremoved from the reactor and no additional distillate was collectedafterwards. The contents in the receiving flask were weighed andisolated for analysis. HPLC quantitative analysis by response factorsfound that the yield of 2,5-dichlorophenol in the distillate was 70.0%.

Example 17: Diazotization/Hydrolysis in Acetic Acid/Sulfuric AcidContaining Sodium Bisulfate

A. Hydrolysis with Water (10% Spiked Sodium Bisulfate)

Diazonium salt solution was prepared as in Example 15-D by the paralleladdition of 2,5-dichloroaniline and sodium nitrite into a mixed solutionof acetic acid and sulfuric acid. The resulting diazonium salt solutionwas evaluated for hydrolysis with water in the presence of sodiumbisulfate spiked in fresh sulfuric acid. The spiked sodium bisulfate wasused to mimic the solvent system that would result from using recycledsulfuric acid in the process of diazotization and hydrolysis.

Diazonium salt solution (0.060 mol, 0.620 mmol/g) was loaded into afirst tared gas-tight syringe equipped with a 14-gauge flexible needletip. Water (57.00 g, 2.85 mol) was loaded into a second tared gas-tightsyringe equipped with a 16-gauge flexible needle tip. Sulfuric acid(96%, 20 g) and sodium bisulfate (2.45 g, 0.34 eq.) were placed in a 500mL three-neck round-bottom flask equipped with a stir bar, a side-armcondenser with receiving flask, a heating mantle, and a JKEMthermocouple. When the acid temperature reached 160° C., the diazoniumsalt solution and water were added in parallel via the two syringepumps. The addition rates were controlled such that the diazonium saltsolution addition was completed in 72 minutes and the water addition wascompleted in 82 minutes. After 90 minutes, the heat was removed from thereactor and no additional distillate was collected afterwards. Thecontents in the receiving flask were weighed and isolated for analysis.HPLC quantitative analysis by response factors found that the yield of2,5-dichlorophenol in the distillate was generally around 88.0%.

B. Diazotization/Hydrolysis (10% Spiked Sodium Bisulfate)

Diazonium salt solution was prepared by parallel addition of2,5-dichloroaniline and sodium nitrite into a mixed solution of aceticacid and sulfuric acid in the presence of spiked sodium bisulfate. Theresulting diazonium salt solution was evaluated for hydrolysis withwater in the presence of sodium bisulfate spiked in fresh sulfuric acid.The spiked sodium bisulfate was used to mimic the solvent system thatwould result from using recycled sulfuric acid in the process ofdiazotization and hydrolysis.

Sulfuric acid (96%, 16.43 g, 2.50 eq.), acetic acid (99%, 22.27 g, 5.70eq.), and sodium bisulfate (0.81 g, 0.10 eq.) were added to a 250 mLthree-neck round-bottom flask equipped with an overhead stirrer. Theflask was cooled in an ice-water bath. A solution of 2,5-dichloroanilinein acetic acid (24.8 wt/wt %, 42.07 g, 0.064 mol) was loaded into atared gas-tight syringe and a solution of sodium nitrite in water (20wt/wt %, 23.25 g, 1.04 eq.) was loaded into a separate syringe pump. Theaddition rates were controlled such that both additions were completedin 90 minutes, during which the reaction internal temperature wasmaintained below 15° C. After the addition, the formed diazonium saltsolution was allowed to come to room temperature.

Diazonium salt solution (0.059 mol, 0.615 mmol/g) was loaded into afirst tared gas-tight syringe equipped with a 14-gauge flexible needletip. Water (53.00 g, 2.65 mol) was loaded into a second tared gas-tightsyringe equipped with a 16-gauge flexible needle tip. Sulfuric acid(96%, 20 g) and sodium bisulfate (2.45 g, 0.33 eq.) were placed in a 500mL three-neck round-bottom flask equipped with a stir bar, a side-armcondenser with receiving flask, a heating mantle, and a JKEMthermocouple. When the acid temperature reached 160° C., the diazoniumsalt solution and water were added in parallel via the aforementionedtwo syringe pumps. The addition rates were controlled such that thediazonium salt solution addition was completed in 72 minutes and thewater addition was completed in 82 minutes. After 90 minutes, the heatwas removed from the reactor and no additional distillate was collectedafterwards. The contents in the receiving flask were weighed andisolated for analysis. HPLC quantitative analysis by response factorsfound that the yield of 2,5-dichlorophenol in the distillate was 82.0%.

The experiments were repeated to show the consistent high yields ofhydrolysis with water in the presence of sodium bisulfate spiked infresh sulfuric acid. The results are shown in Table 17.

TABLE 17 Diazotization/Hydroxylation in Acetic Acid/Sulfuric Acid withSpiked Sodium Bisulfate DCP DCP Exp. Diazotization Hydrolysis purityyield No. H₂SO₄ source H₂SO₄ source/spiked NaHSO₄ (area %) (%) A-1 freshfresh H₂SO₄/10.9% spiked 98.3 88.2 NaHSO₄ A-2 fresh fresh H₂SO₄/10.9%spiked 98.5 87.5 NaHSO₄ A-3 fresh fresh H₂SO₄/10.9% spiked 99.0 88.1NaHSO₄ B fresh/spiked fresh H₂SO₄/10.9% spiked 98.5 82.0 NaHSO₄ NaHSO₄

Example 18: Diazotization/Hydrolysis in Acetic Acid/Recycled SulfuricAcid

A study was conducted to evaluate the feasibility of recycling thesulfuric acid used during the hydrolysis step and reusing that sulfuricacid in the diazotization/hydroxylation process steps. Results of thestudy indicate that the final product 2,5-dichlorophenol had consistentpurities and yields when recycled sulfuric acid was used in the process.Such an approach for a commercial-scale process would be economicallydesirable.

A. Recycle of Sulfuric Acid from the Hydrolysis Reactor

After removing the heating mantle, the hydrolysis reactor was allowed tocome to room temperature. The reactor was weighed and contents werepoured or scraped into a 125 mL Erlenmeyer flask. The reactor was rinsedwith a portion of xylenes and the xylene wash was added to the flask.The flask was heated to 100° C. and stirred for 15 minutes. The xylenewas separated from the aqueous phase. The aqueous phase in the flask wastreated with another portion of xylenes (100° C., 15 minutes) and thexylene was separated from the aqueous phase. The aqueous portion wascooled to room temperature for 1 hour. The sodium bisulfate salts thatcrashed out of solution were isolated by vacuum filtration on a sinteredglass funnel. The solids were washed with a portion of xylenes. Thesalts were placed in a vacuum oven at 40° C. for 24 hours. After drying,the weight loss was measured and recorded. The filtrate was partitionedand the aqueous phase was isolated. The aqueous mixture was analyzed forwater, sodium and sulfate content. The mixture had a composition ofabout 65% sulfuric acid, about 6% sodium bisulfate and about 29% water.The mixture was subjected to concentration or used directly forhydrolysis of diazonium salt in the next cycle.

B. Concentration of Recycled Sulfuric Acid

After the sulfuric acid was recycled from the hydrolysis reactor, asdescribed in Example 18-A, the aqueous filtrate was subjected toconcentration. The filtrate was transferred to a 100 mL three-neckround-bottom flask equipped with a stir bar, a side-arm condenser withreceiving flask, a heating mantle, and a JKEM thermocouple. The contentsin the reactor were gradually heated to 185° C., during which somedistillation occurred. When the reactor temperature reached 185° C.,vacuum was applied in a gentle mode first to prevent bumping andfollowed by slowly reducing the pressure to about 15 torr. The decreasedtemperature was observed during the active distillation. After no moredistillation was observed at the reactor temperature of 185° C., bothheating and vacuum were stopped. The concentrated sulfuric acid had acomposition of about 90% sulfuric acid, about 2% water, and about 8%NaHSO4. The concentrated sulfuric acid was used in the nextdiazotization reaction.

C. Diazotization Using Recycled and Concentrated Sulfuric Acid

Recycled and concentrated sulfuric acid (approximately 90%, 15.25 g,0.14 mol, 2.16 eq.) and glacial acetic acid (99%, 22.99 g, 0.38 mol,5.89 eq.) were added to a 250 mL three-neck round-bottom flask equippedwith an overhead stirrer. The flask was cooled in an ice-water bath. Asolution of 2,5-dichloroaniline in acetic acid (25 wt/wt %, 42.29 g,0.065 mol) and a solution of sodium nitrite in water (20 wt/wt %, 23.84g, 1.07 eq.) were added in parallel via two syringe pumps. The additionrates were controlled such that both additions were completed in 90minutes, during which the reaction internal temperature was maintainedbelow 15° C. After the addition, the formed diazonium salt solution wasallowed to come to room temperature.

D. Hydrolysis Using Recycled Sulfuric Acid

Diazonium salt solution (0.059 mol, 0.621 mmol/g) was loaded into afirst tared gas-tight syringe equipped with a 14-gauge flexible needletip. Water (50.22 g, 2.51 mol) was loaded into a second tared gas-tightsyringe equipped with a 16-gauge flexible needle tip. Recycled sulfuricacid (about 65%, 29.66 g) was placed to a 500 mL three-neck round-bottomflask equipped with a stir bar, a side-arm condenser with receivingflask, a heating mantle, and a JKEM thermocouple. When the acidtemperature reached 160° C., the diazonium salt solution and water wereadded in parallel via two syringe pumps. The addition rates werecontrolled such that the diazonium salt solution addition was completedin 60 minutes and the water addition was completed in 70 minutes. Thedistillation head maximum temperature reached 110° C. The reactor washeated when the distillation head temperature dropped below 90° C. andno additional distillate was collected at the end of approximately 80minutes. The contents in the receiving flask were weighed and isolatedfor analysis. 2,5-Dichlorophenol residue was present in the distillationapparatus so the apparatus was rinsed with methanol. The washings werecollected and quantified. HPLC quantitative analysis by response factorsfound that the yield of 2,5-dichlorophenol in the distillate was 88.5%and the yield of recovered 2,5-dichlorophenol from the apparatus rinsewas 2.11%.

E. Diazotization/Hydrolysis Using Recycled Sulfuric Acid (Cycles)

The diazotization using recycled and concentrated sulfuric acid andhydrolysis using recycled sulfuric acid, as described in Examples 18-Cand 18-D, were repeated for 7 cycles. Both purity and yield of2,5-dichlorophenol in each cycle were evaluated. Results were presentedin Table 18 and show both purities and yields were maintained for eachcycle.

TABLE 18 Purity and Yield of 2,5-Dichlorophenol using Recycled SulfuricAcid Hydrolysis DCP DCP Diazotization Recycled H₂SO₄ source purity yieldCycle H₂SO₄ source (H₂SO₄, NaHSO₄, H₂O) (area %) (%) 1Recycle/concentrate 57.95%, 7.51%, 34.54% 97.3 86.4 2Recycle/concentrate 57.95%, 7.51%, 34.54% 98.3 84.6 3Recycle/concentrate 57.95%, 7.51%, 34.54% 98.9 83.1 4Recycle/concentrate 61.13%, 9.12%, 29.75% 96.4 86.3 5Recycle/concentrate 61.13%, 9.12%, 29.75% 96.6 85.9 6Recycle/concentrate 61.13%, 9.12%, 29.75% 98.9 90.6 7Recycle/concentrate 61.13%, 9.12%, 29.75% 97.4 84.3

All references (patent and non-patent) cited above are incorporated byreference into this patent application. The discussion of thosereferences is intended merely to summarize the assertions made by theirauthors. No admission is made that any reference (or a portion of anyreference) is relevant prior art (or prior art at all). Applicantsreserve the right to challenge the accuracy and pertinence of the citedreferences.

1-27. (canceled)
 28. A process for the preparation of a compoundcorresponding in structure to Formula (VI):

or a salt thereof, the process comprising: contacting a compoundcorresponding in structure to Formula (III-a):

or a salt thereof, with a diazotizing agent in a reaction mediumcomprising sulfuric acid and an organic acid selected from the groupconsisting of C₂-C₆-alkanoic acids and halo-C₁-C₆-alkanoic acids togenerate a diazonium product mixture comprising a compound correspondingin structure to Formula (IV-a):

or a salt thereof; hydrolyzing the compound or salt of Formula (IV-a) togenerate a phenol product mixture comprising a compound corresponding instructure to Formula (V-a):

or a salt thereof; and carboxylating the compound or salt of Formula(V-a) to generate a carboxylated product mixture comprising a compoundcorresponding in structure to Formula (V-b):

or a salt thereof; and converting the compound or salt of Formula (VI-b)to the compound or salt of Formula (VI), wherein the converting stepcomprises: methylating the compound or salt of Formula (V-b) to generatea methylated product mixture comprising a compound corresponding instructure to Formula (V-c):

or a salt thereof; and selectively demethylating the compound or salt ofFormula (V-c) to generate a dicamba product mixture comprising thecompound or salt of Formula (VI); or the converting step comprises:selectively methylating the compound or salt of Formula (V-b) togenerate a dicamba product mixture comprising the compound or salt ofFormula (VI).
 29. The process of claim 28, wherein the converting stepcomprises: methylating the compound or salt of Formula (V-b) to generatea methylated product mixture comprising a compound corresponding instructure to Formula (V-c):

or a salt thereof; and selectively demethylating the compound or salt ofFormula (V-c) to generate a dicamba product mixture comprising thecompound or salt of Formula (VI).
 30. The process of claim 28, whereinthe converting step comprises: selectively methylating the compound orsalt of Formula (V-b) to generate a dicamba product mixture comprisingthe compound or salt of Formula (VI).
 31. The process of claim 29,wherein the process comprises concurrently introducing the diazotizingagent and a solution comprising the organic acid and the compound orsalt of Formula (III) into the reaction medium.
 32. The process of claim29, wherein the process comprises: forming a reaction medium comprisingsulfuric acid; an organic acid selected from the group consisting ofC₂-C₆-alkanoic acids and halo-C₁-C₆-alkanoic acids; and the compound orsalt of Formula (III-a); and introducing into the reaction medium adiazotizing agent to generate a diazonium product mixture comprising thecompound or salt of Formula (IV-a).
 33. The process of claim 29, whereinthe process comprises: forming a reaction medium comprising sulfuricacid; an organic acid selected from the group consisting ofC₂-C₆-alkanoic acids and halo-C₁-C₆-alkanoic acids; and, optionally, afirst amount of the compound or salt of Formula (III-a); and introducinginto the reaction medium a second amount of the compound or salt of thecompound of Formula (III), and a diazotizing agent, to generate adiazonium product mixture comprising the compound or salt of Formula(IV-a).
 34. The process of claim 29 wherein the organic acid is selectedfrom the group consisting of acetic acid and trifluoroacetic acid. 35.The process of claim 34 wherein the organic acid is acetic acid.
 36. Theprocess of claim 29 wherein the diazotizing agent introduced into thereaction medium is nitrosylsulfuric acid.
 37. The process of claim 29wherein the diazotizing agent introduced into the reaction medium is analkali metal nitrite.
 38. The process of claim 37 wherein thediazotizing agent comprises sodium nitrite or calcium nitrite.
 39. Theprocess of claim 29 wherein the process comprises concurrentlyintroducing the diazotizing agent, the organic acid, and the compound orsalt of Formula (III-a) into the reaction medium.
 40. The process ofclaim 29 wherein the molar ratio of the organic acid to the sulfuricacid is from about 30:1 to about 1:10.
 41. The process of claim 29wherein the process further comprises adding a quenching agent to thediazonium product mixture in an amount sufficient to decompose anyremaining diazotizing agent prior to the hydrolyzing step.
 42. Theprocess of claim 29 wherein the compound or salt of Formula (IV-a) isnot isolated from the diazonium product mixture prior to beinghydrolyzed, and the process comprises hydrolyzing the compound or saltof Formula (IV-a) contained in the diazonium product mixture to generatea phenol product mixture comprising the compound or salt of Formula(V-a).
 43. The process of claim 29 wherein the hydrolyzing stepcomprises subjecting the diazonium product mixture to steam distillationto generate the phenol product mixture comprising the compound or saltof Formula (V-a).
 44. The process of claim 43 wherein the phenol productmixture resulting from the steam distillation is a distillate comprisingthe organic acid, water, and the compound or salt of Formula (V-a). 45.The process of claim 44 wherein the process further comprises recoveringthe organic acid from the distillate and recycling the recovered organicacid to a prior process step.
 46. The process of claim 29 wherein theprocess further comprises recovering sulfuric acid from the hydrolysisstep and recycling the recovered sulfuric acid to a prior process step.47. The process of claim 29 wherein the process further comprisesreducing a compound corresponding in structure to Formula (II):

or a salt thereof, to generate the compound or salt of Formula (III-a).48. The process of claim 47 wherein the reducing step is conducted in asolvent comprising the organic acid used in the diazotizing step. 49.The process of claim 47 wherein the process further comprises recoveringthe organic acid from the hydrolyzing step and recycling the recoveredorganic acid to the reducing step.